Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer's Disease: Results from a Double-Blind, Placebo-Controlled Trial.
Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer's Disease: Results from a Double-Blind, Placebo-Controlled Trial.
复制标题
DOI：
10.2174/1567205014666170117141330
复制
发表时间：
2017
影响因子：
2.1
通讯作者：
Sabbagh MN
中科院分区：
文献类型：
--
作者：
Decourt B;Drumm-Gurnee D;Wilson J;Jacobson S;Belden C;Sirrel S;Ahmadi M;Shill H;Powell J;Walker A;Gonzales A;Macias M;Sabbagh MN
迄今为止，阿尔茨海默病（AD）尚无法治愈。在β淀粉样蛋白免疫疗法未能达到减缓AD受试者认知能力下降的主要终点之后，抑制β分泌酶BACE1似乎是一种有前途的治疗方法。在 APP23 小鼠中获得的临床前数据表明，抗癌药物沙利度胺可降低大脑 BACE1 和 Aβ 水平。这促使我们开展一项 NIH 支持的 IIa 期临床试验，以测试沙利度胺治疗 AD 的潜力。我们假设沙利度胺可以减少或稳定大脑淀粉样蛋白沉积，与安慰剂治疗的受试者相比，这将导致药物治疗受试者的认知能力下降较慢。这是一项为期 24 周、随机、双盲、安慰剂对照、平行组研究，针对轻度至中度 AD 患者，沙利度胺的剂量方案递增，目标剂量为每天 400 毫克。主要结果指标是通过一系列测试评估的耐受性和认知表现。共有 185 名受试者经过预筛选，其中 25 名受试者被随机分配。样本基线时的平均年龄为 73.64 (±7.20) 岁；平均受教育年限为 14.24 (±2.3) 年；平均 MMSE 评分为 21.00 (±5.32)；平均 GDS 评分为 2.76 (±2.28)。在 25 名参与者中，14 名 (56%) 因不良事件提前终止，大大降低了研究的有效性。此外，由于报告的不良事件，完成研究的患者 (44%) 从未达到 400 毫克/天沙利度胺的估计治疗剂量。试验结束时，认知数据显示治疗组和安慰剂组之间没有差异。这项研究表明 AD 患者对沙利度胺的耐受性较差，并且无法达到足以对 BACE1 产生影响的治疗剂量。由于耐受性差，这项研究未能证明对认知的有益影响。
To date there is no cure for Alzheimer's disease (AD). After amyloid beta immunotherapies have failed to meet primary endpoints of slowing cognitive decline in AD subjects, the inhibition of the beta-secretase BACE1 appears as a promising therapeutic approach. Pre-clinical data obtained in APP23 mice suggested that the anti-cancer drug thalidomide decreases brainBACE1 and Aβ levels. This prompted us to develop an NIH-supported Phase IIa clinical trial to test the potential of thalidomide for AD. We hypothesized that thalidomide can decrease or stabilize brain amyloid deposits, which would result in slower cognitive decline in drug- versus placebo-treated subjects. This was a 24-week, randomized, double-blind, placebo-controlled, parallel group study with escalating dose regimen of thalidomide with a target dose of 400mg daily in patients with mild to moderate AD. The primary outcome measures were tolerability and cognitive performance assessed by a battery of tests. A total of 185 subjects have been pre-screened, out of which25 were randomized. Mean age of the sample at baseline was 73.64 (±7.20) years; mean education was 14.24 (±2.3) years; mean MMSE score was 21.00 (±5.32); and mean GDS score was 2.76 (±2.28).Among the 25 participants, 14 (56%) terminated early due to adverse events, dramatically decreasing the power of the study. In addition, those who completed the study (44%) never reached the estimated therapeutic dose of 400 mg/day thalidomide because of reported adverse events. The cognitive data showed no difference between the treated and placebo groups at the end of the trial. This study demonstrates AD patients have poor tolerability for thalidomide, and are unable to reach a therapeutic dose felt to be sufficient to have effects on BACE1. Because of poor tolerability, this study failed to demonstrate a beneficial effect on cognition.