Development of musculoskeletal toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-month, double-blind, placebo-controlled study
Development of musculoskeletal toxicity without clear benefit after administration of PG-116800, a matrix metalloproteinase inhibitor, to patients with knee osteoarthritis: a randomized, 12-month, double-blind, placebo-controlled study
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DOI：
10.1186/ar2315
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发表时间：
2007-01-01
影响因子：
4.9
通讯作者：
Spector, Tim D.
中科院分区：
文献类型：
--
作者：
Krzeski, Piotr;Buckland-Wright, Chris;Spector, Tim D.
我们进行了一项随机、双盲、安慰剂对照、多中心、平行分组的剂量-反应研究，观察口服基质金属蛋白酶抑制剂PG-116800对轻、中度膝骨性关节炎患者的疗效和安全性。主要疗效终点包括骨关节炎膝关节关节间隙变窄的进展(通过微焦点放射摄影和透视定位测量)，以及症状(疼痛和僵硬)的减轻和/或功能的改善，根据西安大略和麦克马斯特大学骨关节炎指数(WOMAC)测量。401名患者被随机分配到安慰剂(n=80)或PG-116800的四种剂量之一：25 mg(n=81)、50 mg(n=80)、100 mg(n=80)或200 mg(n=80)，每天两次，持续12个月。在研究期间，基于肌肉骨骼不良反应频率的增加，200毫克剂量被停用。经过一年的治疗，安慰剂和PG-116800在膝关节最小关节间隙宽度或WOMAC评分的平均变化方面没有统计学上的显著差异。最常见的不良反应是关节痛(35%)。在一次随访中，23%的可评估患者的任一肩关节活动度测量至少比基线减少了30%。与安慰剂相比，两个最高剂量组的患者活动范围减少的百分比明显更大。13%的患者，其中一半在200毫克组，报告了手部不良事件(水肿、手掌纤维化、Dupuytren痉挛或持续性肌腱厚度或结节)。最常见的三个肩部不良事件是可逆性关节痛、僵硬和肌肉痛，主要影响两个最高剂量组。在膝骨性关节炎患者中，基质金属蛋白酶抑制剂PG-116800的不良风险-收益平衡阻碍了该化合物在该适应症中的进一步发展。这项研究增加了证据的份量，表明基质金属蛋白酶抑制剂的副作用一般使它们不适合用于骨关节炎。
We performed a randomized, double-blind, placebo-controlled, multicenter, parallel-group, dose-response study of the efficacy and safety of the oral administration of PG-116800, a matrix metalloproteinase (MMP) inhibitor, in patients with mild to moderate knee osteoarthritis. The primary efficacy endpoints included the progression of joint space narrowing in the osteoarthritic knee, as measured by microfocal radiography with fluoroscopic positioning, and the reduction of symptoms (pain and stiffness) and/or the improvement of function, as measured by the Western Ontario and McMaster Universities osteoarthritis index (WOMAC). Four hundred and one patients were randomly assigned to either placebo (n = 80) or one of fourdoses of PG-116800: 25 mg (n = 81), 50 mg (n = 80), 100 mg (n = 80), or 200 mg (n = 80) taken twice daily for 12 months. During the study, the 200-mg dose was discontinued based on an increased frequency of musculoskeletal adverse effects. After 1 year of treatment, no statistically significant difference was observed between placebo and PG-116800 with regard to mean changes in minimum joint space width of the knee or to WOMAC scores. The most frequent adverse effect was arthralgia (35%). Twenty-three percent of evaluable patients had at least a 30% decrease from baseline of at least onerange-of-motion measurement of either shoulder at a follow-up visit. The percentage of patients with reduction in range of motion was significantly greater in the two highest dose groups relative to placebo. Thirteen percent of patients, half of whom were in the 200-mg group, reported hand adverse events (oedema, palmar fibrosis, Dupuytren contracture, or persistent tendon thickness or nodules). The three most frequent shoulder adverse events were reversible arthralgia, stiffness, and myalgia, which mostly affected the two highest dose groups. The unfavorable risk-benefit balance of the MMP inhibitor PG-116800 in patients with knee osteoarthritis precludes further development of the compound for this indication. This study adds to the weight of evidence suggesting that side effect profiles of MMP inhibitors in general make them unsuitable for use in osteoarthritis.