Targeting Inflammation using Salsalate in Type 1 Diabetic Neuropathy (TINSAL-T1DN

描述(申请人提供)：糖尿病神经病变(DN)是糖尿病最常见的慢性并发症，最终影响到一半的1型糖尿病(T1 DM)患者，并导致严重发病率、高死亡率、严重肢体残疾、生活质量差，估计每年总成本为220亿美元。由于周围神经系统的复杂结构和解剖，糖尿病肾病具有非常广泛的临床症状和缺陷，包括剧烈疼痛、感觉障碍、足部溃疡和截肢。尽管糖尿病肾病的发病率很高，但大多数评估已建立的糖尿病肾病治疗方法的随机临床试验一直令人失望。到目前为止，还没有针对这种情况的致病治疗方法。糖尿病控制和并发症试验(DCCT)表明，为达到接近正常的血糖而设计的强化控制对于降低1型糖尿病患者发生糖尿病肾病的风险至关重要。然而，尽管可达到的强化血糖控制是必要的，但仍不足以预防神经系统的不良影响，这证明有必要在糖尿病肾病的早期发现新的药物靶点来治疗。实验和临床研究表明，低度炎症和核因子-kB激活在糖尿病肾病的发病机制和与糖尿病肾病相关的疼痛综合征中起重要作用的证据不断涌现。这表明，具有已知抗炎特性的药物，如水杨酸酯，可以防止糖尿病肾病的发展和与糖尿病肾病相关的疼痛。水杨酸盐是一种前药物形式的水杨酸盐，是FDA批准的治疗骨性关节炎和其他风湿病的药物。它是一种高效的阻断IKK2/NF-：B通路的药物，安全边际大，成本低。最近有研究表明，水杨酸盐具有降血糖作用。我们建议开展一项临床试验，以评估水杨酸盐对糖尿病肾病的疗效。 我们的具体目标是：目标1：制定一项多中心随机临床试验的建议，以评估沙柳酸盐对T1 DM患者糖尿病肾病测量的影响。目标2：制定在目标1中进行试验所需的支持材料，制定选址标准，接触感兴趣的地点并最终确定选择过程，并制定一般和地点特定的招募策略。这些目标的实现将允许在计划拨款阶段R34期间对样本受试者实施拟议的临床试验方案以测试文件和程序，并允许提交多中心试验拨款申请。 公共卫生相关性：这项研究与公共健康相关，因为糖尿病神经病变(DN)是糖尿病最常见的慢性并发症，最终影响到一半的糖尿病患者，并导致严重发病率、高死亡率、严重肢体残疾和低生活质量。这与美国国立卫生研究院的任务有关，因为到目前为止，仍没有针对糖尿病肾病的具体治疗方法。我们建议使用FDA批准的一种通常用于治疗骨关节炎的药物，该药物最近被证明具有降糖作用，以解决炎症--糖尿病周围神经损害发生和发展的关键介质，以及疼痛--糖尿病肾病患者最常见和最麻烦的症状。

DESCRIPTION (provided by applicant): Diabetic neuropathy (DN) is the most common chronic complication of diabetes, ultimately affecting half of patients with type 1 diabetes (T1DM) and leading to severe morbidity, high mortality, major physical disability, poor quality of life and estimated total annual costs of $22 billion. Due to the complex structure and anatomy of the peripheral nervous system, DN presents with a very broad spectrum of clinical symptoms and deficits, including severe pain, sensory deficits, foot ulcers and amputations. Despite the high morbidity associated with DN, most randomized clinical trials evaluating therapies for established DN have been disappointing. To date there is no pathogenetic treatment for this condition. The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive control designed to achieve near-normal glycemia is essential in reducing the risk of DN development in type 1 diabetes. However, attainable intensive glycemic control, although necessary, is insufficient to prevent adverse nervous system effects, justifying a therapeutic need to identify new drug targets to treat DN early in its course. Evidence for an important role of low-grade inflammation and of nuclear factor kappa B (NF-kB) activation in the pathogenesis of DN and in the pain syndrome associated with DN is emerging from both experimental and clinical studies. This suggests that agents with known anti-inflammatory properties, such as salicylates, may prevent the development of DN and the pain associated with DN. Salsalate (Disalcid), a pro-drug form of salicylate, is an FDA approved treatment for osteoarthritis and other rheumatologic conditions. It is a highly effective drug in blocking the IKK2/NF-:B pathway, with a large margin of safety, and low cost. Salsalate has recently been shown to have glucose lowering effects. We propose to develop a clinical trial to evaluate the effect of Salsalate on DN. Our specific aims are: Aim 1: Develop a proposal for a multi-center randomized clinical trial to evaluate the effects of salsalate on measures of DN in patients with T1DM Aim 2: Develop the supporting materials needed to conduct the trial in Aim 1, develop the criteria of site selection, reach out to the sites of interest and finalize the selection process, and develop the general and site specific recruitment strategies. The accomplishment of these aims will allow implementing the proposed clinical trial protocol on a sample of subjects to test documents and procedures during the planning grant phase R34 and allow submission of an application for a multi-center trial grant. PUBLIC HEALTH RELEVANCE: This study is relevant to public health because diabetic neuropathy (DN) is the most common chronic complication of diabetes, ultimately affecting half of patients with diabetes and leading to severe morbidity, high mortality, major physical disability, and poor quality of life. This is relevant to the NIH mission because to date there is still no specific treatment for DN. We propose to use a FDA-approved drug commonly used to treat osteoarthritis, which has recently been shown to have glucose lowering effects, to address inflammation - a critical mediator in the development and progression of peripheral nerve damage in diabetes, and pain- the most common and cumbersome symptom for patients with DN.