A Pilot Trial to Assess Low-Intensity Ultrasound in Osteoarthritis

描述（由申请人提供）： 骨关节炎（OA）是最常见的关节炎形式，是一种流行的、使人衰弱的疾病，没有改变疾病进展的治疗方法，目前采用疗效有限的骨关节炎修饰疗法进行管理。我们提出了一项随机、假对照的临床试验，将脉冲低强度超声（PIMUS）作为一种新颖但合理的治疗方法， 从根本上改变OA管理。 OA影响了近2700万美国人，估计每年的成本超过800亿美元。OA的患病率正在迅速增加。据估计，到2030年，约有6000万美国人将受到影响。在军队中患病率更高，使其成为退伍军人事务部特别重要的疾病。OA是老年人下肢疼痛和残疾的主要原因，也是全膝关节置换术（TKR）的主要适应症，在过去十年中，TKR手术的数量增加了一倍多。OA负担的增加主要是因为现有的医疗管理只能解决疼痛，长期疗效最好也是微不足道的。尽管在理解OA的发病机制方面取得了实质性进展，但尚未建立有效的疾病改善干预措施。 退行性关节软骨是OA发病机制的核心，然而，关节软骨的修复能力有限。因此，开发专注于软骨再生和修复策略的OA治疗方法非常重要。大量的临床前工作已经证明了机械刺激对软骨细胞代谢的合成代谢作用。来自临床前和临床骨折以及临床前软骨研究的已发表文献表明， 机械刺激可以通过超声心动图传递。这些一致的积极数据证实，有必要研究超声心动图作为治疗OA的重要干预措施的潜力。 我们提出了一项IIa期、多中心、随机、假对照、平行、双盲试验，其中包括一个随机化前假手术导入期，以确定在早期膝关节OA患者中，作为一种改善症状和结构的干预措施，超声造影是否可能比假手术更有效。将使用FDA批准的已在临床上用于骨折愈合的器械进行超声检查。本研究包括3个阶段：28天筛选期、4周随机化前假手术导入期和48周假手术对照治疗期。这三个招募中心，即湖城、匹兹堡和圣地亚哥退伍军人事务医疗中心，在成功开展OA试验方面具有丰富的经验。在23个月的招募期内，178名符合入选标准的临床和相对早期放射学膝关节OA患者将入组随机化前假导入期。成功完成导入期并继续符合入选标准的共160例患者将被随机分配至假手术对照治疗期。所有患者将在治疗期接受48周随访，这是评估症状缓解（通过OMERACT-OARSI应答者标准评估）和结构改变（通过MRI确定的股骨内侧髁软骨厚度评估）的共同主要结局的时间点。骨关节炎倡议（OAI）的新数据表明，这是一个敏感的 和OA结构进展的具体措施。还将评价创新性和探索性疾病标志物，包括软骨下骨髓病变和OA的可溶性血清和尿液生物标志物，沿着更传统的结局，如WOMAC OA指数和放射学关节间隙狭窄。 支持本研究的临床前数据见研究计划。该项目是一个翻译的板凳到床边的建议，针对高度衰弱，流行，昂贵的疾病，目前的治疗方案是非常有限的。我们在退伍军人事务部的领先OA中心组建了一支优秀的临床科学家协作团队。如果这次干预是 成功并随后在一项关键试验中被证实为OA的有效治疗， 从根本上改变这种高度流行且使人衰弱的疾病的护理标准，可能会改善数千万退伍军人和其他美国人的生活质量。

DESCRIPTION (provided by applicant): Osteoarthritis (OA), the most common form of arthritis, is a prevalent and debilitating disease without therapies that alter disease progress and is currently managed with symptom-modifying therapies that are only modestly effective. We propose a randomized, sham-controlled clinical trial of pulsed low-intensity ultrasound (PLIUS) as a novel yet well-justified treatment that could fundamentally alter OA management. OA affects almost 27 million Americans with an estimated annual cost of over $80 billion. The prevalence of OA is increasing rapidly. Estimates suggest that about 60 million Americans will be affected by 2030. Still greater prevalence is seen in members of the armed services, making it a disease of special importance to the Department of Veterans Affairs. OA is the leading cause of lower extremity pain and disability in older age and is the leading indication for total knee replacement (TKR), with the number of TKR procedures having more than doubled over the last decade. The increasing burden of OA is largely because available medical management addresses only pain with long-term efficacy that is marginal at best. In spite of substantial progress in understanding the pathogenesis of OA, no effective disease modifying interventions have been established. Degenerative articular cartilage is central to the pathogenesis of OA, however, articular cartilage has limited capacity for repair. Thus, the development of OA therapeutics that focus on cartilage regeneration and repair strategies are of great importance. A large body of pre-clinical work has demonstrated the anabolic effect of mechanical stimulation on chondrocyte metabolism. Published literature from pre-clinical and clinical bone fracture and pre-clinical cartilage research indicate that effective mechanical stimulation can be delivered via PLIUS. These consistently positive data affirm the need to investigate the potential of PLIUS as an important intervention for treatment of OA. We propose a Phase IIa, multi-center, randomized, sham-controlled, parallel, double-blind trial with a prerandomization sham run-in period to determine if PLIUS is potentially more effective than sham as a symptom- and structure-modifying intervention in patients with early OA of the knee. PLIUS will be applied using an FDA-approved device already in clinical use for bone fracture healing. The study consists of three periods: a 28-day Screening Period, a four week Prerandomization Sham Run-in Period and a 48-Week Sham-controlled Treatment Period. The three recruiting centers, the Salt Lake City, Pittsburgh, and San Diego Veterans Affairs Medical Centers, have extensive experience in successfully conducting OA trials. Over a 23-month recruitment period, 178 patients with clinical and relatively early stage radiographic knee OA meeting entry criteria will be enrolled into the pre-randomization sham run- in period. A total of 160 patients who successfully completed the run-in period and continue to meet entry criteria will be randomized into the sham-controlled treatment period. All patients will be followed in the treatment period for 48 weeks, which is the time point for assessment of the co-primary outcomes of symptom relief, as assessed by the OMERACT-OARSI Responder Criteria, and structural modification, as assessed by MRI-determined medial femoral condyle cartilage thickness. Emerging data from the Osteoarthritis Initiative (OAI) suggests that this is a sensitive and specific measure for structural progression of OA. Innovative and exploratory disease markers, including subchondral bone marrow lesions and soluble serum and urine biomarkers for OA will also be evaluated, along with more traditional outcomes such as the WOMAC OA Index and radiographic joint space narrowing. The pre-clinical data supporting this study are described in the Research Plan. This project is a translational bench-to-bedside proposal targeting a highly debilitating, prevalent, and costly disease for which current treatment options are exceedingly limited. We have assembled an outstanding collaborative team of clinical scientists in leading OA centers within the Department of Veterans Affairs. If this intervention is successful and subsequently confirmed as an effective treatment for OA in a pivotal trial, it could fundamentally change the standard of care for this highly prevalent and debilitating disease, potentially improving the quality of life for tens of millions of veterans and other Americans.