Phased Exploratory Clinical Studies of Harpagophytum procumbens’ Impact upon the Biological Signature of Inflammatory Osteoarthritis

 描述(由申请人提供)：肌肉骨骼疾病是疼痛、功能丧失和医疗保健支出的主要来源，每年花费美国人数十亿美元。患有慢性疼痛的人会求助于综合健康做法，以补充其他传统的医疗治疗，或者当他们的疼痛对药物产生抵抗力或努力避免药物的副作用时。然而，这种做法的安全性、有效性和机制的科学证据是有限的。欧洲的临床研究已经提供了证据，证明植物学上的直立哈帕根草(H.provumbens或魔爪)对许多患有关节炎和慢性下腰痛的患者是安全和有效的。然而，天然产物的可变性，以及缺乏明确的生物学特征，需要对具有良好特征的产品进行额外的探索性研究，以便能够进行适当的方法学严谨的后续临床研究。拟议的项目将使用一种具有良好特性的产品来评估假想的作用机制的生物签名。拟议项目的R21阶段将着眼于以下目标：(1)进一步定义非肠道和肠道制剂中具有良好特性的普鲁穆本斯水乙醇提取物的主要次级代谢物的生物利用度和短期药动学；(2)确定普鲁穆本斯提取物在四周剂量下在早期炎症性膝骨性关节炎患者中的生物学特征和假想作用机制；以及(3)制定规程、数据和安全监测计划以及操作/程序手册，并获得R33阶段所有必要的监管批准。在成功完成R21阶段之后，将在R33阶段处理以下目标：(1)确认和扩展对上述全身性炎症生物标记物的影响的评估，以及在12周内服用两种剂量之一的患者关节液中上述全身性炎症生物标记物和生物标记物的生物标记物；(2)评估全身和局部关节生物标记物水平变化与临床结果(疼痛、僵硬、功能困难)之间的关系。这项研究的完成将确保未来的临床试验能够以适当评估H.proumbens产品的有效性所需的方法严谨性和结果措施进行。

 DESCRIPTION (provided by applicant): Musculoskeletal conditions represent a major source of pain, loss of function, and health care expenditure that costs Americans many billions, yearly. People with conditions causing chronic pain turn to integrative health practices to supplement other conventional medical treatment, or when their pain is resistant to or in an effort to avoid side effects of medications. However, scientific evidence of safety, efficacy and mechanisms of such practices are limited. European clinical research has provided evidence for safety and efficacy of the botanical Harpagophytum procumbens (H. procumbens or Devil's Claw) for many patients suffering from arthritis and chronic low back pain. The variability in the natural products, however, and lack of a well-defined biological signature necessitate additional exploratory studies with well-characterized products, so that subsequent clinical studies of appropriate methodological rigor can be conducted. The proposed project will use a well characterized product to assess a biological signature for a hypothesized mechanism of action. The R21 phase of the proposed project will address the following objectives: (1) further define the bioavailability and short term pharmacokinetics of the principal secondary metabolites of a well-characterized aqueous-ethanolic extract of H. procumbens in non-enteric and enteric formulations; (2) define the biological signature and hypothetical mechanism of action of the H. procumbens extract in patients with early stage inflammatory knee osteoarthritis over four week dosing; and, (3) develop protocol, data and safety monitoring plan and manual of operations/procedures and obtain all necessary regulatory approvals for the R33 phase. Following successful completion of the R21 phase, the following objectives will be addressed during the R33 phase: (1) confirm and extend assessment of the impact of the H. procumbens extract upon the biological signature of the above referenced systemic inflammatory biomarkers and biomarkers in synovial fluid of patients consuming either of two doses over twelve weeks; and, (2) evaluate the relationship between changes in systemic and local joint biomarker levels and clinical outcomes (pain, stiffness, functional difficulty). Completion of this study will ensure that future clinical trials can be conducted with the methodological rigor and outcome measures needed to appropriately evaluate the effectiveness of H. procumbens products.