Renal Associates, San Antonio, TX 78215, USA.
N Engl J Med. 2011 Jul 28;365(4):327-36. doi: 10.1056/NEJMoa1105351. Epub 2011 Jun 24.
Chronic kidney disease (CKD) associated with type 2 diabetes is the leading cause of kidney failure, with both inflammation and oxidative stress contributing to disease progression. Bardoxolone methyl, an oral antioxidant inflammation modulator, has shown efficacy in patients with CKD and type 2 diabetes in short-term studies, but longer-term effects and dose response have not been determined.
In this phase 2, double-blind, randomized, placebo-controlled trial, we assigned 227 adults with CKD (defined as an estimated glomerular filtration rate [GFR] of 20 to 45 ml per minute per 1.73 m(2) of body-surface area) in a 1:1:1:1 ratio to receive placebo or bardoxolone methyl at a target dose of 25, 75, or 150 mg once daily. The primary outcome was the change from baseline in the estimated GFR with bardoxolone methyl, as compared with placebo, at 24 weeks; a secondary outcome was the change at 52 weeks.
Patients receiving bardoxolone methyl had significant increases in the mean (±SD) estimated GFR, as compared with placebo, at 24 weeks (with between-group differences per minute per 1.73 m(2) of 8.2±1.5 ml in the 25-mg group, 11.4±1.5 ml in the 75-mg group, and 10.4±1.5 ml in the 150-mg group; P<0.001). The increases were maintained through week 52, with significant differences per minute per 1.73 m(2) of 5.8±1.8 ml, 10.5±1.8 ml, and 9.3±1.9 ml, respectively. Muscle spasms, the most frequent adverse event in the bardoxolone methyl groups, were generally mild and dose-related. Hypomagnesemia, mild increases in alanine aminotransferase levels, and gastrointestinal effects were more common among patients receiving bardoxolone methyl.
Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks. The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD. (Funded by Reata Pharmaceuticals; BEAM ClinicalTrials.gov number, NCT00811889.).
与 2 型糖尿病相关的慢性肾脏病（CKD）是导致肾衰竭的主要原因，炎症和氧化应激均会导致疾病进展。口服抗氧化炎症调节剂 bardoxolone 甲酯在短期研究中已显示出对 CKD 和 2 型糖尿病患者的疗效，但长期效果和剂量反应尚未确定。
在这项 2 期、双盲、随机、安慰剂对照试验中，我们将 227 名 CKD 成人（定义为估计肾小球滤过率[GFR]为 20 至 45ml/分钟/1.73m2 体表面积）以 1:1:1:1 的比例随机分配至安慰剂组或 bardoxolone 甲酯组，目标剂量分别为 25、75 或 150mg 每日一次。主要终点是与安慰剂相比，bardoxolone 甲酯在 24 周时对估计 GFR 的变化；次要终点是 52 周时的变化。
与安慰剂组相比，接受 bardoxolone 甲酯治疗的患者估计 GFR 有显著升高，24 周时的平均值（±SD）分别为每分钟每 1.73m2 8.2±1.5ml（25mg 组、11.4±1.5ml（75mg 组）和 10.4±1.5ml（150mg 组）；P<0.001）。这些增加在第 52 周时保持不变，每分钟每 1.73m2 的差异分别为 5.8±1.8ml、10.5±1.8ml 和 9.3±1.9ml。肌肉痉挛是 bardoxolone 甲酯组最常见的不良事件，通常为轻度且与剂量相关。接受 bardoxolone 甲酯治疗的患者中，低镁血症、丙氨酸氨基转移酶水平轻度升高和胃肠道反应更为常见。
bardoxolone 甲酯可改善 24 周时患有晚期 CKD 和 2 型糖尿病患者的估计 GFR。这种改善在 52 周时持续存在，表明 bardoxolone 甲酯可能有望用于治疗 CKD。（由 Reata 制药公司资助；BEAM ClinicalTrials.gov 编号，NCT00811889。）
