Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Astellas Pharma Global Development, Astellas Pharma Europe BV, Leiden, Netherlands.
Lancet Diabetes Endocrinol. 2018 Dec;6(12):925-933. doi: 10.1016/S2213-8587(18)30289-4. Epub 2018 Nov 6.
Many patients with diabetic kidney disease have residual albuminuria and are at risk of disease progression. The ALBUM trial investigated the efficacy of a novel, orally active inhibitor of vascular adhesion protein-1, ASP8232, compared with placebo for reducing albuminuria in individuals with type 2 diabetes and chronic kidney disease.
In this randomised, double-blind, placebo-controlled phase 2 trial, we randomly assigned individuals (aged 18-85 years) from 64 clinical sites in nine European countries to receive ASP8232 40 mg or placebo orally once daily for 12 weeks using a web-based randomisation schedule (block size 4), stratified by country. Eligible patients had a urinary albumin-to-creatinine ratio (UACR) of 200-3000 mg/g, an estimated glomerular filtration rate of at least 25 mL/min per 1·73 m but lower than 75 mL/min per 1·73 m, HbA less than 11·0% (97 mmol/mol), and stable treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antidiabetic medication for 3 months or more. The primary endpoint was mean change from baseline to week 12 in log-transformed first morning void UACR, which was assessed in all patients who received at least one dose of study drug and had at least one post-baseline UACR measurement (full analysis set). Safety was assessed in all patients who received at least one dose of study drug. Participants and investigators were masked to treatment allocation. This trial is registered with ClinicalTrials.gov, number NCT02358096.
125 participants were randomly assigned to receive ASP8232 (n=64) or placebo (n=61), of whom 120 (60 in each group) were included in the full analysis set; all participants were assessed for safety endpoints. At 12 weeks, UACR decreased by 17·7% (95% CI 5·0 to 28·6) in the ASP8232 group and increased by 2·3% (-11·4 to 18·1) in the placebo group; the placebo-adjusted difference between groups was -19·5% (95% CI -34·0 to -1·8; p=0·033). 39 (61%) patients in the ASP8232 group and 34 (56%) patients in the placebo group had a treatment-emergent adverse event, of which 16 in the ASP8232 group and four in the placebo group were drug-related. The most frequently reported adverse events that were possibly drug-related in the ASP8232 group were renal impairment (five patients) and decreased eGFR (three patients); in the placebo group, no single drug-related treatment-emergent adverse event was reported by more than one participant.
ASP8232 is effective in reducing albuminuria in patients with diabetic kidney disease and is safe and well tolerated. These findings warrant further research to ascertain the effect of ASP8232 on delaying progression of diabetic kidney disease.
Astellas.
许多患有糖尿病肾病的患者仍存在白蛋白尿，存在疾病进展的风险。ALBUM 试验研究了一种新型、口服活性的血管黏附蛋白-1 抑制剂 ASP8232 与安慰剂相比，在 2 型糖尿病和慢性肾脏病患者中降低白蛋白尿的疗效。
在这项随机、双盲、安慰剂对照的 2 期试验中，我们从欧洲 9 个国家的 64 个临床中心随机分配年龄在 18-85 岁之间的个体（n=125）接受 ASP8232（40mg，每天一次）或安慰剂口服治疗，为期 12 周，使用基于网络的随机分组方案（分组大小为 4），分层因素为国家。合格患者的尿白蛋白与肌酐比值（UACR）为 200-3000mg/g，估算肾小球滤过率（eGFR）至少为 25mL/min/1.73m2，但低于 75mL/min/1.73m2，HbA1c<11.0%（97mmol/mol），并且稳定接受血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂和抗糖尿病药物治疗 3 个月或以上。主要终点是自基线至第 12 周时首次晨尿 UACR 的平均变化，该变化在接受至少一剂研究药物且至少有一次基线后 UACR 测量值的所有患者中进行评估（全分析集）。所有接受至少一剂研究药物的患者均进行安全性评估。参与者和研究者对治疗分配情况不知情。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT02358096。
125 名参与者被随机分配接受 ASP8232（n=64）或安慰剂（n=61）治疗，其中 120 名（每组各 60 名）被纳入全分析集；所有参与者均进行了安全性终点评估。在 12 周时，ASP8232 组的 UACR 降低了 17.7%（95%CI 5.0 至 28.6），安慰剂组增加了 2.3%（-11.4 至 18.1）；安慰剂调整后的组间差异为-19.5%（95%CI -34.0 至 -1.8；p=0.033）。ASP8232 组有 39 名（61%）患者和安慰剂组有 34 名（56%）患者出现治疗相关不良事件，其中 ASP8232 组中有 16 名和安慰剂组中有 4 名与药物相关。在 ASP8232 组中，可能与药物相关的最常报告的不良事件是肾功能损害（5 名患者）和 eGFR 降低（3 名患者）；在安慰剂组中，没有任何一种药物相关的治疗出现的不良事件被报告的患者超过 1 名。
ASP8232 可有效降低糖尿病肾病患者的白蛋白尿，且安全且耐受良好。这些发现值得进一步研究，以确定 ASP8232 对延缓糖尿病肾病进展的影响。
安斯泰来。
