Medical Director, Medical Department, Noscira SA, Madrid, Tres Cantos, Spain.
J Alzheimers Dis. 2013;33(1):205-15. doi: 10.3233/JAD-2012-120805.
This pilot, double-blind, placebo-controlled, randomized, escalating dose trial explored the safety and efficacy of tideglusib, an inhibitor of glycogen synthase kinase-3, in Alzheimer's disease (AD) patients. Thirty mild-moderate AD patients on cholinesterase inhibitor treatment were administered escalating doses (400, 600, 800, 1,000 mg) of tideglusib or placebo (ratio 2 : 1) for 4, 4, 6, and 6 weeks, respectively. The primary objective was to evaluate the safety and tolerability of tideglusib with strict criteria for drug escalation or withdrawal. Mini-Mental Status Examination (MMSE), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog+), word fluency, Geriatric Depression Scale (GDS), and a final Global Clinical Assessment (GCA) were assessed as secondary objectives. Treatment was well tolerated. Adverse events were as frequent in active and placebo groups, except for some moderate, asymptomatic, and fully reversible increases (>2.5 × ULN) of serum transaminases in 6 active cases (p = 0.001). Tideglusib produced positive trends in MMSE, ADAS-cog, GDS, and GCA without statistical significance in this small sample. Responders in MMSE were significantly higher in the active group (p = 0.05). Patients escalated up to 1000 mg/day had a benefit of 1.68 points in the MMSE and 4.72 points in the ADAS-cog+ when compared to placebo. This small pilot study provides valuable safety and efficacy estimates for the treatment of AD patients with tideglusib, currently being confirmed in a larger clinical trial. Due to escalating doses and the small sample size, this trial provides insufficient evidence to support or reject a benefit of tideglusib in AD.
本试验为一项初步的、双盲、安慰剂对照、随机、递增剂量的试验，旨在探索糖原合酶激酶-3 抑制剂 tideglusib 治疗阿尔茨海默病（AD）患者的安全性和有效性。30 名正在接受胆碱酯酶抑制剂治疗的轻中度 AD 患者，按 2:1 的比例随机分为两组，分别接受递增剂量（400、600、800、1000mg）的 tideglusib 或安慰剂治疗，分别持续 4、4、6、6 周。主要目标是采用严格的药物递增或停药标准，评估 tideglusib 的安全性和耐受性。次要目标是评估简易精神状态检查（MMSE）、阿尔茨海默病评估量表认知分量表（ADAS-cog+）、词语流畅性、老年抑郁量表（GDS）和最终的总体临床评估（GCA）。治疗耐受良好。除了 6 例活性组患者出现一些中度、无症状和完全可逆的血清转氨酶升高（>2.5×正常值上限[ULN]）（p=0.001）外，活性组和安慰剂组的不良事件发生率相当。在这个小样本中，tideglusib 治疗在 MMSE、ADAS-cog、GDS 和 GCA 方面呈现出积极趋势，但无统计学意义。在 MMSE 中，活性组的应答者明显更高（p=0.05）。与安慰剂相比，每天递增至 1000mg 剂量的患者，MMSE 评分提高了 1.68 分，ADAS-cog+评分提高了 4.72 分。这项小型试验为 tideglusib 治疗 AD 患者提供了有价值的安全性和疗效估计，目前正在更大的临床试验中得到证实。由于剂量递增和样本量小，该试验提供的证据不足以支持或否定 tideglusib 在 AD 中的获益。
