The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial
The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial
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DOI：
10.1016/s2213-8587(15)00261-2
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发表时间：
2015-09-01
影响因子：
44.5
通讯作者：
Schall, Thomas J.
中科院分区：
文献类型：
--
作者：
de Zeeuw, Dick;Bekker, Pirow;Schall, Thomas J.
背景：尽管使用血管紧张素转换酶（ACE）抑制剂或血管紧张素受体阻滞剂（ARBs）进行最佳治疗，2型糖尿病合并肾病患者仍有较高的心肾发病率和死亡率。残留风险与残留蛋白尿有关。我们评估了CCX140-B，一种C-C趋化因子受体2型（CCR2）的选择性抑制剂，在给予标准治疗（包括ACE抑制剂或arb）的同时，是否可以进一步减少蛋白尿。在这项随机、双盲、安慰剂对照的临床试验中，我们从比利时、捷克共和国、德国、匈牙利、波兰和英国的78个研究中心招募了患者。我们招募了年龄在18-75岁的2型糖尿病患者，伴有蛋白尿（第一次早晨空尿白蛋白与肌酐比值[U-ACR] 100-3000 mg/g），肾小球滤过率估计为每1.73 m(2) 25 mL/min或更高，并且在研究开始前至少8周服用稳定的抗糖尿病治疗和ACE抑制剂或arb。根据基线U-ACR和肾功能（估计肾小球滤过率）对患者进行分层，然后通过最小化算法的交互式网络反应系统随机分配（1:1:1）至口服安慰剂，5 mg CCX140-B或10 mg CCX140-B，每天一次。最初方案中的12周给药期通过方案修订延长至52周。主要疗效指标是修改意向治疗人群（所有不间断给药的患者，不包括在第12周永久停止给药的患者，或由于延迟批准方案修订而暂时停止给药的患者）中52周内U-ACR的基线变化。我们对所有随机分配的接受至少一剂研究药物的患者进行了安全性分析。根据预先设定的分析计划，我们对主要终点进行单侧统计检验，计算活性组与对照组差异的95%置信限。研究从2011年12月7日（首名患者入组）开始，至2014年8月4日结束。我们招募了332名患者：111名被分配接受安慰剂，110至5mg CCX140-B和111至10mg CCX140-B。其中，192人被纳入改良意向治疗人群。在52周内，安慰剂组的U-ACR从基线变化为-2% (95% CI -11%至9%)，5 mg CCX140-B组为-18%(-26%至-8%)，10 mg CCX140-B组为-11%（-20%至-1%）。我们记录了5 mg CCX140-B与安慰剂之间-16%的差异（单侧95%置信上限-5%；p=0.01）， 10 mg CCX140-B与安慰剂之间-10%的差异（95%置信上限2%；p=0.08）。安慰剂组111例患者中有81例（73%）发生不良事件，而CCX140-B 5 mg组110例患者中有71例（65%）发生不良事件，CCX140-B 10 mg组111例患者中有68例（61%）发生不良事件；研究期间未发生肾脏事件。我们的数据表明，在目前2型糖尿病和肾病患者的标准护理中，CCX140-B抑制CCR2具有肾脏保护作用。
Background Patients with type 2 diabetes and nephropathy have high cardiorenal morbidity and mortality despite optimum treatment including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Residual risk is related to residual albuminuria. We assessed whether CCX140-B, a selective inhibitor of C-C chemokine receptor type 2 (CCR2), could further reduce albuminuria when given in addition to standard care, including ACE inhibitors or ARBs.Methods In this randomised, double-blind, placebo-controlled clinical trial, we recruited patients from 78 research centres in Belgium, Czech Republic, Germany, Hungary, Poland, and the UK. We enrolled patients with type 2 diabetes aged 18-75 years with proteinuria (first morning void urinary albumin to creatinine ratio [U-ACR] 100-3000 mg/g), estimated glomerular filtration rate of 25 mL/min per 1.73 m(2) or higher, and taking stable antidiabetic treatment and ACE inhibitors or ARBs, for at least 8 weeks before study entry. Patients were stratified based on baseline U-ACR and renal function (estimated glomerular filtration rate), and then randomly assigned (1: 1: 1) via an interactive web response system with a minimisation algorithm to oral placebo, 5 mg CCX140-B, or 10 mg CCX140-B once a day. The 12-week dosing period in the initial protocol was extended to 52 weeks by protocol amendment. The primary efficacy measure was change from baseline in U-ACR during 52 weeks in the modified intention-to-treat population (all patients with uninterrupted dosing, excluding patients who stopped dosing at week 12 either permanently under the original protocol, or temporarily because of delay in approval of the protocol amendment). We did safety analyses on all randomly assigned patients who received at least one dose of study drug. According to a prespecified analysis plan, we analysed the primary endpoint with one-sided statistical testing with calculation of upper 95% confidence limits of the differences between active and control.Findings The study ran from Dec 7, 2011 (first patient enrolled), until Aug 4, 2014. We enrolled 332 patients: 111 were assigned to receive placebo, 110 to 5 mg CCX140-B, and 111 to 10 mg CCX140-B. Of these, 192 were included in the modified intention-to-treat population. U-ACR changes from baseline during 52 weeks were -2% for placebo (95% CI -11% to 9%), -18% for 5 mg CCX140-B (-26% to -8%), and -11% for 10 mg CCX140-B (-20% to -1%). We recorded a -16% difference between 5 mg CCX140-B and placebo (one-sided upper 95% confidence limit -5%; p=0.01) and a -10% difference between 10 mg CCX140-B and placebo (upper 95% confidence limit 2%; p=0.08). Adverse events occurred in 81 (73%) of 111 patients in the placebo group versus 71 (65%) of 110 patients in the CCX140-B 5 mg group and 68 (61%) of 111 patients in the CCX140-B 10 mg group; there were no renal events during the study.Interpretation Our data suggest that CCR2 inhibition with CCX140-B has renoprotective effects on top of current standard of care in patients with type 2 diabetes and nephropathy.