Topiramate as a Disease Altering Therapy for CSPN

托吡酯作为 CSPN 的疾病改变疗法

• 批准号: 9254145
• 负责人: CHRISTOPHER S. COFFEY
• 金额: $ 239.92万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9254145
• 关键词: Address; Adult; Affect; Age; Algorithms; American; Animal Model; Anticonvulsants; Axon; Behavioral; Biological Markers; Blood Glucose; Body Weight decreased; Brief Pain Inventory; Central obesity; Characteristics; Clinical; Clinical Trials; Counseling; Cutaneous; DNA; Data; Development; Diabetes Mellitus; Diabetes prevention; Diabetic Neuropathies; Diet; Disease; Distal; Dose; Dyslipidemias; Epilepsy; Equilibrium; Etiology; Evaluation; Exercise; FDA approved; Fiber; Functional disorder; Funding; Future; Genes; Glucose; Goals; Hypertension; Hypertriglyceridemia; Injury; Insulin; Insulin Resistance; Link; Lipids; Literature; Measures; Medical; Metabolic; Metabolic syndrome; Metabolism; Migraine; Morbidity - disease rate; National Institute of Neurological Disorders and Stroke; Natural History; Nerve; Nerve Fibers; Nerve Regeneration; Neuropathy; Obesity; Oral; Outcome; Outcome Measure; Pain; Pain quality; Participant; Pathogenesis; Patient Care; Patient Outcomes Assessments; Patient-Focused Outcomes; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacology; Phentermine; Physiology; Placebos; Play; Prediabetes syndrome; Protocols documentation; Punch Biopsy; Quality of life; Randomized; Randomized Controlled Trials; Research; Research Design; Risk; Role; Seizures; Sensory; Signs and Symptoms; Skin; Sodium Channel; Symptoms; Testing; Therapeutic; Thigh structure; Treatment Efficacy; Utah; Variant; Walking; Weight; animal data; bariatric surgery; base; clinically relevant; clinically significant; density; diabetic; diabetic patient; effective intervention; effective therapy; equilibration disorder; experience; fall risk; falls; gain of function; gain of function mutation; impaired glucose tolerance; improved; injured; innovation; insulin sensitivity; lifestyle intervention; nerve conduction study; painful neuropathy; peripheral nerve regeneration; phase II trial; pill; prevent; primary outcome; randomized placebo controlled trial; regenerative; reinnervation; secondary outcome; sensory neuropathy; sugar; topiramate; treatment response; treatment strategy; voltage

Cryptogenic sensory peripheral neuropathy (CSPN) affects 5-10% of those over 40 years old, resulting in reduced quality of life due to pain, sensory loss, imbalance, and fall related injuries. CSPN is a significant cause of patient morbidity, for which there exists no disease altering therapy. Clinically similar to early diabetic neuropathy, it is characterized by preferential injury to small axons, and frequently results in prominent sensory loss and neuropathic pain. Injury to small axons is reflected in reduced intraepidermal nerve fiber density (IENFD). While the precise etiology of CSPN is unknown, and likely multifactorial, accumulating evidence indicates that obesity, dyslipidemia, and insulin resistance/prediabetes (metabolic syndrome) are linked to CSPN risk. Patients with CSPN have an elevated risk of metabolic syndrome and patients with prediabetes have an elevated risk of CSPN. Obesity and dyslipidemia also significantly increase the risk of neuropathy among diabetic patients. Animal models support the hypothesis that obesity and prediabetic levels of glucose dysregulation cause neuropathy. A growing literature suggests that exercise improves nerve regenerative capacity, results in increased IENFD and improves neuropathic pain among patients with CSPN and prediabetes. Cumulatively, these data support the hypothesis that metabolic syndrome is linked to neuropathy risk, CSPN is potentially reversible, and aggressive metabolic management may be an effective strategy to enhance nerve regeneration and improve patient symptoms. However, currently available lifestyle interventions are very difficult to employ in a clinical setting due to poor compliance and attrition from the necessary behavioral changes. Development of better pharmacologic approaches is a major priority. Recent data suggest that gain of function in voltage gated sodium channels plays a role in CSPN and other common forms of neuropathy. Topiramate is a promising therapeutic approach to CSPN. Clinical trials of this anticonvulsant agent in diabetic neuropathy suggest improvement in pain and quality of life, and also in measures of peripheral nerve function including sensory testing and IENFD. Topiramate has multiple potentially neuroprotective effects. It induces significant weight loss at the dose proposed in this study, and also improves insulin resistance. These effects are greatest among obese patients. Topiramate also blocks voltage gated sodium channels. It has been extensively studied for the treatment of epilepsy and migraine and is generally safe and well tolerated. Several studies suggest a potential benefit for neuropathic pain associated with diabetic neuropathy. Small studies suggest topiramate therapy not only results in improved pain, but also improves QOL and preferentially impacts measures of small fiber function, including an increase in IENFD. Data from animal models of diabetes also support its potential therapeutic efficacy. While topiramate has multiple potential mechanisms of action (weight loss, improved insulin sensitivity, sodium channel modulation), the fact that each would be expected to have benefit in CSPN and its potential to differentially impact small fiber injury, which is characteristic of CSPN, support its further evaluation as a disease altering therapy. The Topiramate for CSPN (TopCSPN) Study will randomize 125 CSPN patients to 100 mg of topiramate daily or matched placebo. Treatment will last 24 months. IENFD and the Norfolk Quality of Life – Diabetic Neuropathy (NQOL-DN) will be co-primary outcome measures. A major secondary goal of the TopCSPN study is to evaluate the clinical meaning of IENFD and other commonly employed surrogate measures of neuropathy. The results of the CSPN Study promise to immediately impact patient care and facilitate future peripheral neuropathy clinical trials.

隐性感觉周围神经病（CSPN）影响40岁以上的患者中的5-10％，导致 疼痛，感觉丧失，失衡和跌倒有关的伤害降低了生活质量。 CSPN是重要的 病人发病的原因，没有改变治疗的疾病。临床上类似于早期糖尿病 神经病，其特征是对小轴突的偏好损伤，并且经常导致突出的感觉 损失和神经性疼痛。小轴突的损伤反映在降低的皮肤内神经纤维密度中 （IENFD）。虽然CSPN的精确病因尚不清楚，并且可能是多因素的，积累了证据 表明肥胖，血脂异常和胰岛素抵抗/前糖尿病（代谢综合征）与 CSPN风险。 CSPN患者患有代谢综合征的风险升高，患有糖尿病前期患者 CSPN风险升高。肥胖和血脂异常也大大增加了神经病的风险 在糖尿病患者中。动物模型支持肥胖症和葡萄糖前糖尿病前水平的假设 失调引起神经病。越来越多的文献表明，运动可以改善神经的再生 能力，导致IENFD增加并改善CSPN患者的神经性疼痛 糖尿病。累积地，这些数据支持代谢综合征与神经病有关的假设 风险，CSPN可能可逆，积极的代谢管理可能是一个有效的策略 增强神经再生并改善患者症状。但是，目前可用的生活方式干预措施 由于依从性不佳和必要的损耗，在临床环境中很难在临床环境中使用 行为改变。开发更好的药理学方法是重中之重。最新数据暗示 电压门控钠通道中功能的增长在CSPN和其他常见形式中起作用 神经病。托吡酯是CSPN的有前途的治疗方法。这种抗惊厥药的临床试验 糖尿病神经病中的药物表明疼痛和生活质量的改善以及测量 外周神经功能，包括感觉测试和IENFD。托吡酯具有多重潜力 神经保护作用。它在本研究中提出的剂量下诱导了重大减肥，也可以改善 胰岛素抵抗。这些影响在肥胖患者中最大。托吡酯还阻塞电压门控 钠通道。它已被广泛研究用于治疗癫痫和偏头痛，通常是 安全且耐受性良好。几项研究表明，与 糖尿病神经病。小型研究表明，托型酯治疗不仅会改善疼痛，还会导致 改善QOL并优先影响小纤维功能的度量，包括IENFD的增加。 来自糖尿病动物模型的数据还支持其潜在疗法。 topramate拥有 多种潜在的作用机制（减肥，改善胰岛素灵敏度，钠通道调制）， 期望每个人都会受益于CSPN及其对小小的影响的潜力，这一事实 CSPN的特征纤维损伤支持其进一步的评估作为改变疾病的治疗。 CSPN（TOPCSPN）研究的托吡酯将每天将125例CSPN患者随机为100毫克的托吡酯或 匹配的安慰剂。治疗将持续24个月。 IENFD和诺福克生活质量 - 糖尿病神经病 （NQOL-DN）将是共同的结果指标。 TOPCSPN研究的主要次要目标是 评估IENFD的临床含义和其他常用的神经病替代措施。 CSPN研究的结果有望立即影响患者护理并促进未来的周围 神经病临床试验。