Daily & Localized NSAID Sonophoresis for Symptomatic Treatment of Knee Osteoarthritis

项目总结： 骨关节炎(OA)是最常见的关节炎类型，#年影响美国3000多万成年人 2015年，根据美国疾病控制和预防中心的数据，这一比例超过25% 预防和国家卫生研究院。超过40%的65岁以上的人有症状的骨性关节炎和 由于疾病导致行动不便。骨性关节炎的疼痛通常通过保守的治疗方法来缓解，例如 水疗、散步、骑自行车和药物。经常使用非甾体抗炎药可能会对 心血管、胃肠和肾脏系统。因此，外用非甾体抗炎药经常被使用，并提供类似的 口服非甾体类抗炎药可缓解疼痛。长时间超声波已被用于减轻疼痛和改善关节功能 膝关节骨性关节炎患者。当超声波与外用药物联合使用时，声导疗法会推动 分子深入组织，与单独使用超声波或局部使用相比，可提供更好的止痛效果 单独应用非甾体抗炎药。在我们的SBIR第一阶段，我们开发了一种长时间低强度超声非甾体抗炎药- 增强型(1%双氯芬酸)超声导入贴片，供老年骨性关节炎人群使用。我们首先证明了 超声导入贴片可使非甾体抗炎药(包括水杨酸)的组织渗透率提高3.5倍和 与护理标准相比，双氯芬酸减少了3.8倍(p&lt；0.01)。其次，对超声导入贴片进行了评估 一项20名受试者的人为因素研究和一项32名受试者的临床研究，研究对象为放射学确诊的骨性关节炎患者 轻至中度膝骨性关节炎。仅在每天使用4小时的7天内，症状性疼痛显著减少 应答者2.96分(70%)NRS(n=24，p&lt；0.001)，所有受试者2.03分(50%)NRS(n=32，p=0.02)。 超过95%的研究人群发现该设备易于使用，并将继续治疗他们的膝盖骨关节炎 症状。对于此第二阶段续订申请(1)First ZetrOZ Systems将改进设计并优化 针对老龄化人口的保质期稳定性和设备功能/可用性的超声波导入补丁。一系列 监管测试标准，包括敏化、细胞毒性、包装/制剂稳定性、生物兼容性、 微生物的生长、保质期和家庭使用将在超声导入贴片上完成。另外，一头猪 将完成带组织病理学的动物模型，以验证该装置的安全性。(2)ZetrOZ系统 将完成一项为期8周、3支手臂、多地点、安慰剂对照、随机、疗效的研究，以扩展我们的 第一阶段研究：在300名患者中检查超声导入贴片的健康益处和商业化程度 在三个种族不同的地方注册。研究的主要结果将是疼痛评分，评估 每天使用数字评级量表(NRS)。基线NRS评分将包括研究的前两周 没有干预的情况下。干预阶段将分离人口统计上相等的三个100人的群体， 被分配每天使用主动/安慰剂超声波导入贴片或标准双氯芬酸局部乳膏 申请了六个星期。建议的联合疗法有可能提供一种安全、有效和 老年性骨性关节炎的保守治疗方法。

Project Summary: Osteoarthritis (OA) is the most common type of arthritis, affecting over 30 million adults in the United States in 2015 and represents over 25% of medical office visits according to the Centers for Disease Control and Prevention and the National Institutes of Health. Over 40% of individuals over 65 have symptomatic OA and reduced mobility due to the disease. OA pain is often mitigated with conservative treatment approaches such as water therapy, walking, cycling, and pharmaceuticals. Regular use of NSAIDs can have adverse side effects on cardiovascular, gastrointestinal and renal systems. As such, topical NSAIDs are often used and provide similar pain relief to oral NSAIDs. Long-duration ultrasound has been used to reduce pain and improve joint function in patients with knee OA. When ultrasound is used in conjunction with topical pharmaceuticals, sonophoresis drives the molecules deeper into tissue, providing improved pain relief compared to ultrasound alone or topical application of NSAIDs alone. In our SBIR Phase I, we developed a long-duration low-intensity ultrasound NSAID- enhanced (1% diclofenac) sonophoresis patch for use by the aging OA population. We first demonstrated that the sonophoresis patch could increase tissue penetration of NSAIDs including salicylic acid by 3.5x and diclofenac by 3.8x compared to standard of care (p<0.01). Secondly, the sonophoresis patch was evaluated in a 20-subject human-factors study, and a 32-subject OA clinical study on patients with radiographically confirmed mild to moderate knee OA. In only 7-days of daily 4-hour use, symptomatic pain was significantly reduced by 2.96 point (70%) NRS (n=24, p<0.001) for responders and 2.03 point (50%) NRS (n=32, p=0.02) for all subjects. Over 95% of the study population found the device easy to use and would continue treatment for their knee OA symptoms. For this Phase II renewal application (1) First ZetrOZ Systems will refine the design and optimize the sonophoresis patch for shelf-life stability and device functionality/usability by the aging population. A series of regulatory testing standards including sensitization, cytotoxicity, packaging/formulation stability, biocompatibility, microbial growth, shelf-life and home-use will be completed on the sonophoresis patch. Additionally, a porcine animal model with histopathology will be completed to verify the safety profile of the device. (2) ZetrOZ Systems will complete an 8-week, 3-arm, multi-site, placebo-controlled, randomized, efficacy study to expand upon our Phase I study by examining the health benefits and commerciality of the sonophoresis patch in 300 patients enrolled at three ethnically diverse locations. The primary outcome of the study will be pain score, evaluated daily using the numerical rating scale (NRS). Baseline NRS score will include the first two weeks of the study without intervention. The intervention phase will separate three demographically equivalent groups of 100, assigned to use either the active/placebo sonophoresis patch or standard diclofenac topical cream daily self- applied for six weeks. The proposed combination therapy has the potential to deliver a safe, effective, and conservative treatment approach for OA in the aging population.