A Randomized, Double-Blind, Delayed Treatment, Placebo-Controlled Trial to Assess the Changes in Multi-parametric MRI in Patients With Acute Demyelinating Lesions Taking Clemastine Fumarate as a Myelin Repair Therapy
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 入组人数
- 44
- 试验地点
- 1
- 主要终点
- Corpus Callosum Myelin Water Fraction
研究概览
简要总结
The clinical trial is intended to assess for clinical evidence of Clemastine Fumarate as a myelin repair therapy in patients with acute inflammatory injury-causing demyelination as measured by multi-parametric MRI assessments.
No reparative therapies exist for the treatment of acute demyelinating lesions. Clemastine fumarate was identified along with a series of other antimuscarinic medications as a potential remyelinating agent using the micropillar screen (BIMA) developed at the University of California, San Francisco (UCSF). Following in vivo validation, an FDA IND exemption was granted to investigate clemastine for the treatment of multiple sclerosis in the context of chronic optic neuropathy. That pilot study was recently completed and is the first randomized control trial documenting efficacy for a putative remyelinating agent for the treatment of MS. The preselected primary efficacy endpoint (visual evoked potential) was met and a strong trend to benefit was seen for the principal secondary endpoint assessing function (low contrast visual acuity). That trial number was 13-11577.
This study seeks to follow up on that study and examine clemastine fumarate's protective and reparative effects in the context of acute demyelinating brain lesions as imaged by multi-parametric MRI assessments. The investigators will be assessing the effects of clemastine fumarate as a remyelinating therapy and assessing its effect on MRI metrics of lesions found in patients with a confirmed diagnosis of acute inflammatory injury-causing demyelination.
In addition to using conventional multi-parametric MRI assessments, this study will also evaluate a new MRI technique called Ultrashort Echo Time (UTE) MRI to assess the effects of clemastine fumarate as a remyelinating therapy of acute lesions found in patients with a confirmed diagnosis of acute inflammatory injury-causing demyelination and compare it to the other assessments.
详细描述
Treatments capable of remyelination are a major unmet need for demyelinating diseases that involve myelin damage, loss, or dysfunction in the central nervous system (CNS). Acute demyelination of axons is believed to be injurious to neurons and serves as a major contributor to irreversible cell loss that underlies permanent disability. Available treatments are primarily immunosuppressing, without directly addressing or fully preventing axonal degeneration and disability. Clemastine fumarate was identified along with a series of other antimuscarinic medications as a potential remyelinating agent using the micropillar screen (BIMA) developed at UCSF. The screen demonstrated that clemastine promoted the differentiation of the endogenous oligodendrocyte precursor cells (OPCs) into mature myelinating oligodendrocytes. Following in vivo validation, an FDA investigational new drug (IND) exemption was granted to investigate clemastine for the treatment of multiple sclerosis in the context of chronic optic neuropathy. That pilot study was recently completed and is the first randomized control trial documenting efficacy for a putative remyelinating agent for the treatment of MS. The preselected primary efficacy endpoint (visual evoked potential) was met and a strong trend to benefit was seen for the principal secondary endpoint assessing function (low contrast visual acuity). That trial number was 13-11577.
This clinical trial is intended to assess magnetic resonance imaging evidence of remyelination using Clemastine Fumarate in patients with acute demyelinated lesions. Specifically speaking, the primary objective will assess various multi-parametric MRI sequences on the corpus callosum region, a region that animal models studies identified as a promising candidate for assessing remyelination. The aim was to help define the potential for MRI in measuring remyelination in acute lesions, determine the optimal sequences and location for measuring myelin recovery, and help guide trial design for future remyelinating trials. Finally, the study is designed to assess tolerability and clinical efficacy of Clemastine using outcomes intended to assess for (a) adverse events and (b) recovery of myelin.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent must be obtained prior to any assessment being performed.
- •Patients diagnosed with relapsing remitting multiple sclerosis and a disease duration of < 15 years
- •Male or female patients aged 18-55 years (inclusive)
- •Use of appropriate contraception during period of trial (women). Before entry women must be:
- •Post-menopausal for at least 1 year OR
- •Surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, male partner vasectomy or otherwise incapable of pregnancy) OR
- •Practicing a highly effective method of birth control if sexually active, including hormonal prescription oral contraceptives, contraceptive injections, contraceptive patch, intrauterine device, double barrier method (e.g., condoms, diaphragm or cervical cap with spermicidal foam, cream or gel), or male partner sterilization consistent with local regulations regarding use of birth control methods for patients participating in clinical trials, for the duration of their participation in the study OR
- •Not heterosexually active (patients who are not heterosexually active at screening must agree to utilize a highly effective method of birth control if they become heterosexually active during their participation in the study) OR
- •Practicing true abstinence (when this is in line with the preferred and usual lifestyle of the subject) Period abstinence (e.g., calendar, ovulation, symptothermal, post ovulation methods) is not an acceptable method.
排除标准
- •Radiologic identification of marked brain atrophy relative to patients age based on recent MRI and interpretation of expert neuroradiologist or PI
- •New lesion in most recent MRI (within 3 months)
- •Hypersensitivity to clemastine or other arylalkylamine antihistamines, or any of the excipients.
- •Treatment with corticosteroids within 30 days prior to screening.
- •Expanded Disability Status Scale (EDSS) ≥ 4.5
- •History of significant cardiac conduction block.
- •History of cancer.
- •Suicidal ideation or behavior in 6 months prior to baseline.
- •Pregnancy, breastfeeding or planning to become pregnant.
- •Involved with other study protocols simultaneously without prior approval.
- •Concomitant use of any other putative remyelinating therapy as determined by the investigator.
- •Prior treatment with total lymphoid irradiation, T cell or T cell receptor vaccination.
- •Prior treatment with alemtuzumab, mitoxantrone, or cyclophosphamide.
- •Serum creatinine > 1.5 mg/dL; aspartate transaminase (AST), alanine transaminase (ALT), or alkaline phosphatase > 2 times the upper limit of normal. (Reported within 72 hours)
- •History of drug or alcohol abuse within the past year.
- •Untreated B12 deficiency (as determined by B12 serological assessments and metabolites including methylmalonic acid [MMA] and homocysteine) or untreated hypothyroidism.
- •Clinically significant cardiac, metabolic, hematologic, hepatic, immunologic, urologic, endocrinologic, neurologic, pulmonary, psychiatric, dermatologic, allergic, renal, or other major diseases that in the PI's judgment may affect the interpretation of study results or patient safety.
- •History of or presence of clinically significant medical illness or laboratory abnormality that, in the opinion of the investigator would preclude participation in the study
- •Inability to participate in MRI, including extreme claustrophobia.
- •Any dental braces or permanent or undetachable metals in the jaw or face.
研究组 & 干预措施
Clemastine 12 mg, then clemastine 8 mg, then Placebo
Group 1 will receive the treatment (clemastine) for the first 90 days. They will receive clemastine 12 mg for 14 days followed by clemastine 8 mg for 76 days, and then switch to the placebo (a sugar pill) for the remaining 90 days
干预措施: Clemastine Fumarate (Drug)
Clemastine 12 mg, then clemastine 8 mg, then Placebo
Group 1 will receive the treatment (clemastine) for the first 90 days. They will receive clemastine 12 mg for 14 days followed by clemastine 8 mg for 76 days, and then switch to the placebo (a sugar pill) for the remaining 90 days
干预措施: Placebo (Drug)
Placebo, then Clemastine 12 mg, then Clemastine 8 mg
Group 1 will receive the placebo for the first 90 days. Then, they will switch to clemastine (treatment) for 90 days. They will receive clemastine 12 mg for 14 days followed by clemastine 8 mg for the remaining 76 days.
干预措施: Clemastine Fumarate (Drug)
Placebo, then Clemastine 12 mg, then Clemastine 8 mg
Group 1 will receive the placebo for the first 90 days. Then, they will switch to clemastine (treatment) for 90 days. They will receive clemastine 12 mg for 14 days followed by clemastine 8 mg for the remaining 76 days.
干预措施: Placebo (Drug)
结局指标
主要结局
Corpus Callosum Myelin Water Fraction
时间窗: This will be assessed at the baseline visit.
The efficacy of clemastine relative to placebo at increasing the myelin water fraction (MWF) (measured in %) from magnetic resonance imaging of the corpus callosum.
Change from Baseline in Corpus Callosum Myelin Water Fraction at 3 Months
时间窗: This will be assessed at the baseline and 3 month visits.
The efficacy of clemastine relative to placebo at increasing the myelin water fraction (MWF) (measured in %) from magnetic resonance imaging of the corpus callosum. Change = (3-month % - Baseline %)
Change from Baseline in Corpus Callosum Myelin Water Fraction at 6 Months
时间窗: This will be assessed at the baseline and 6 month visits.
The efficacy of clemastine relative to placebo at increasing the myelin water fraction (MWF) (measured in %) from magnetic resonance imaging of the corpus callosum. Change = (6-month % - Baseline %)
Change from Baseline in Corpus Callosum UTE Fraction at 3 Months
时间窗: This will be assessed at the baseline and 3-month visits.
The efficacy of clemastine relative to placebo at increasing the ultrashort echo time (UTE) fraction (measured in %) derived from magnetic resonance imaging of the corpus callosum. Change = (3-month % - Baseline %)
Corpus Callosum T1 Relaxation Time
时间窗: This will be assessed at the baseline visit.
The efficacy of clemastine relative to placebo at shortening the T1 relaxation time (measured in seconds) within the corpus callosum using T1 mapping protocols in an MRI.
Change from Baseline in Corpus Callosum T1 Relaxation Time at 6 Months
时间窗: This will be assessed at the baseline and 6-month visits.
The efficacy of clemastine relative to placebo at shortening the T1 relaxation time (measured in seconds) within the corpus callosum using T1 mapping protocols in an MRI. (6-month time - Baseline time)
Change from Baseline in Corpus Callosum T1 Relaxation Time at 3 Months
时间窗: This will be assessed at the baseline and 3-month visits.
The efficacy of clemastine relative to placebo at shortening the T1 relaxation time (measured in seconds) within the corpus callosum using T1 mapping protocols in an MRI. (3-month time - Baseline time)
Corpus Callosum UTE Fraction
时间窗: This will be assessed at the baseline visit.
The efficacy of clemastine relative to placebo at increasing the ultrashort echo time (UTE) fraction (measured in %) derived from magnetic resonance imaging of the corpus callosum.
Change from Baseline in Corpus Callosum UTE Fraction at 6 Months
时间窗: This will be assessed at the baseline and 6-month visits.
The efficacy of clemastine relative to placebo at increasing the ultrashort echo time (UTE) fraction (measured in %) derived from magnetic resonance imaging of the corpus callosum. Change = (6-month % - Baseline %)
次要结局
- Change from Baseline in Optic Radiation T1 Relaxation time at 3 Months(This will be assessed at the baseline and 3-month visits.)
- Change from Baseline in Optic Radiation T1 Relaxation time at 6 Months(This will be assessed at the baseline and 6-month visits.)
- Corticospinal Tract T1 Relaxation Time(This will be assessed at the baseline visit.)
- Change from Baseline in Corticospinal Tract T1 Relaxation Time at 3 Months(This will be assessed at the baseline and 3-month visits.)
- Change from Baseline in Corticospinal Tract T1 Relaxation Time at 6 Months(This will be assessed at the baseline and 6-month visits.)
- Optic radiation UTE Fraction(This will be assessed at the baseline visit.)
- Change from Baseline in Optic radiation UTE Fraction at 3 Months(This will be assessed at the baseline and 3-month visits.)
- Change from Baseline in Optic Radiation Myelin Water Fraction at 3 Months(This will be assessed at the baseline and 3-month visits.)
- Change from Baseline in Optic Radiation Myelin Water Fraction at 6 Months(This will be assessed at the baseline and 6-month visits.)
- Corticospinal Tract Myelin Water Fraction(This will be assessed at the baseline visit.)
- Change from Baseline in Corticospinal Tract Myelin Water Fraction at 3 Months(This will be assessed at the baseline and 3-month visits.)
- Change from Baseline in Corticospinal Tract Myelin Water Fraction at 6 Months(This will be assessed at the baseline and 6-month visits.)
- Optic Radiation T1 Relaxation time(This will be assessed at the baseline visit.)
- Optic Radiation Myelin Water Fraction(This will be assessed at the baseline visit.)
- Change from Baseline in Optic radiation UTE Fraction at 6 Months(This will be assessed at the baseline and 6-month visits.)
- Corticospinal Tract UTE Fraction(This will be assessed at the baseline visit.)
- Change from Baseline in Corticospinal Tract UTE Fraction at 3 Months(This will be assessed at the baseline and 3-month visits.)
- Change from Baseline in Corticospinal Tract UTE Fraction at 6 Months(This will be assessed at the baseline and 6-month visits.)
- Change from Baseline in LOI T1 Relaxation Time at 6 Months(This will be assessed at the baseline and 6-month visits.)
- Lesion of interest (LOI) MWF(This will be assessed at the baseline visit.)
- Change from Baseline in Lesion of interest (LOI) MWF at 3 Months(This will be assessed at the baseline and 3-month visits.)
- Change from Baseline in Lesion of interest (LOI) MWF at 6 Months(This will be assessed at the baseline and 6-month visits.)
- LOI T1 Relaxation Time(This will be assessed at the baseline visit.)
- Change from Baseline in LOI T1 Relaxation Time at 3 Months(This will be assessed at the baseline and 3-month visits.)
- LOI UTE Fraction(This will be assessed at the baseline visit.)
- Change from Baseline in LOI UTE Fraction at 3 Months(This will be assessed at the baseline and 3-month visits.)
- Change from Baseline in LOI UTE Fraction at 6 Months(This will be assessed at the baseline and 6-month visits.)
- Whole Brain MWF(This will be assessed at the baseline visit.)
- Change from Baseline in Whole Brain MWF at 3 Months(This will be assessed at the baseline and 3-month visits.)
- Change from Baseline in Whole Brain MWF at 6 Months(This will be assessed at the baseline and 6-month visits.)
- Whole Brain T1 Relaxation Time(This will be assessed at the baseline visit.)
- Change from Baseline in Whole Brain T1 Relaxation Time at 3 Months(This will be assessed at the baseline and 3-month visits.)
- Change from Baseline in Whole Brain T1 Relaxation Time at 6 Months(This will be assessed at the baseline and 6-month visits.)
- Whole Brain UTE Fraction(This will be assessed at the baseline visit.)
- Change from Baseline in Whole Brain UTE Fraction at 3 Months(This will be assessed at the baseline and 3-month visits.)
- Change from Baseline in Whole Brain UTE Fraction at 6 Months(This will be assessed at the baseline and 6-month visits.)
- Clemastine Tolerability(This will be assessed at the baseline visit.)
- Change from Baseline in Clemastine Tolerability at 3 Months(This will be assessed at the baseline and 3-month visits.)
- Change from Baseline in Clemastine Tolerability at 6 Months(This will be assessed at the baseline and 6-month visits.)