A Pilot Trial to Assess Low-Intensity Ultrasound in Osteoarthritis

评估低强度超声治疗骨关节炎的试点试验

• 批准号: 9174071
• 负责人: DANIEL O CLEGG
• 金额: --
• 依托单位: VA SALT LAKE CITY HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-10-01 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174071
• 关键词: Address; Affect; Age; American; Animal Experimentation; Arthritis; Basic Science; Biological Markers; Bone Marrow; Cartilage; Cavia; Chondrocytes; Cities; Clinic; Clinical; Clinical Data; Clinical Trials; Controlled Clinical Trials; Cost of Illness; Data; Degenerative polyarthritis; Development; Devices; Diagnostic radiologic examination; Disease; Disease Marker; Double-blind trial; Engineering; Enrollment; FDA approved; Fracture; Fracture Healing; Gold; Human; Image; Individual; Intervention; Investigation; Joints; Knee; Knee Osteoarthritis; Lesion; Light; Literature; Lower Extremity; Magnetic Resonance Imaging; Measures; Mechanical Stimulation; Mechanics; Medial; Medical; Medical center; Metabolism; Military Personnel; Modality; Modeling; Modification; Morphology; Nature; Orthopedics; Outcome; Pain; Pain management; Pathogenesis; Patients; Phase; Physiologic pulse; Placebos; Prevalence; Procedures; Production; Publishing; Quality of life; Randomized; Recruitment Activity; Research; Running; Scientist; Serum; Services; Severities; Sodium Chloride; Sonication; Structure; Symptoms; System; Therapeutic; Thick; Time; Ultrasonography; Urine; Veterans; Weight-Bearing state; Western Ontario and McMaster Universities Arthritis Index; Work; articular cartilage; attenuation; base; bench to bedside; cartilage degradation; cartilage regeneration; cartilage repair; cost; disability; effective therapy; experience; improved; indexing; innovation; interest; knee pain; knee replacement arthroplasty; meetings; member; novel; pilot trial; portability; pre-clinical; preclinical study; primary outcome; public health relevance; reduce symptoms; repaired; response; screening; standard of care; subchondral bone; symptomatic improvement; treatment duration; treatment group; treatment response

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.

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、使人虚弱的疾病，没有改变疾病进展的治疗方法，目前只能通过症状修改疗法进行治疗，但效果不大。我们提出了一种随机、假对照的脉冲低强度超声(PLIUS)临床试验，作为一种新的但合理的治疗方法，可以 从根本上改变办公自动化管理。OA影响了近2700万美国人，估计每年的成本超过800亿美元。骨性关节炎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。在武装部队成员中的流行率更高，使其成为退伍军人事务部特别重要的疾病。骨性关节炎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，TKR手术的数量在过去十年中增加了一倍多。OA负担的增加在很大程度上是因为现有的医疗管理只能解决疼痛问题，其长期疗效充其量是微乎其微的。尽管在理解骨性关节炎的发病机制方面取得了实质性进展，但还没有建立有效的疾病调节干预措施。关节软骨退变是骨性关节炎发病机制的核心，但关节软骨的修复能力有限。因此，发展以软骨再生和修复策略为重点的骨性关节炎治疗方法具有重要意义。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。临床前和临床前骨折以及临床前软骨研究发表的文献表明， 机械刺激可以通过Plius传递。这些一贯积极的数据表明，有必要研究PLIUS作为治疗骨性关节炎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，在预随机化假磨合期，以确定PLIUS作为膝关节早期骨关节炎患者的症状和结构修改干预是否潜在比假手术更有效。PLIUS将使用FDA批准的已经用于骨折愈合的临床设备。这项研究包括三个阶段：28天的筛查期，四周的随机前假磨合期和48周的假对照治疗期。盐湖城、匹兹堡和圣地亚哥退伍军人事务医疗中心这三个招募中心在成功进行OA试验方面拥有丰富的经验。在23个月的招募期间，178名临床和相对早期的膝关节骨关节炎放射学符合入选标准的患者将被纳入随机前的假磨合期。共有160名成功完成磨合期并继续符合入选标准的患者将随机进入假对照治疗期。所有患者将在为期48周的治疗期间接受随访，这是根据OMERACT-OARSI Responder标准评估症状缓解和结构调整的共同主要结果的时间点，根据MRI确定的股骨内侧髁软骨厚度评估结构改变。来自骨关节炎倡议(OAI)的新数据表明，这是一种敏感的 以及针对骨关节炎结构性进展的具体措施。还将评估创新和探索性疾病标记物，包括软骨下骨髓损害和骨关节炎的可溶性血清和尿液生物标记物，以及更传统的结果，如WOMAC骨关节炎指数和放射学关节间隙狭窄。支持这项研究的临床前数据描述在研究计划中。该项目是一项针对一种高度虚弱、流行和昂贵的疾病的转化性长凳到床边建议，目前对这种疾病的治疗选择极其有限。我们在退伍军人事务部内领先的办公自动化中心组建了一支出色的临床科学家协作团队。如果这次干预是 成功并随后在关键试验中被确认为治疗骨性关节炎的有效方法，它可能 从根本上改变这种高度流行和令人衰弱的疾病的护理标准，潜在地改善数千万退伍军人和其他美国人的生活质量。