From the Keck School of Medicine of the University of Southern California (L.S.S.), Los Angeles; Avraham Pharmaceuticals, Ltd (Y.G.), Yavne; Bar Ilan University (J.R.), Ramat Gan, Israel; University of California (R.G.T.), San Diego; Department of Neurology (R.S., S.R.), Medical University, Graz, Austria; and Hebrew University (M.W.), Jerusalem, Israel.
Neurology. 2019 Oct 8;93(15):e1474-e1484. doi: 10.1212/WNL.0000000000008239. Epub 2019 Sep 6.
Ladostigil reduces oxidative stress and microglial activation in aging rats. We assessed its safety and potential efficacy in a 3-year, randomized, double-blind, placebo-controlled phase 2 clinical trial in patients with mild cognitive impairment (MCI) and medial temporal lobe atrophy.
Patients 55 to 85 years of age with MCI, Clinical Dementia Rating (CDR) score of 0.5, Mini-Mental State Examination (MMSE) score >24, Wechsler Memory Scale-Revised Verbal Paired Associates I score ≤18, and Medial Temporal Lobe Atrophy Scale score >1 were stratified by ε4 genotype and randomly assigned (1:1) to ladostigil 10 mg/d or placebo. Primary outcomes were safety and onset of Alzheimer disease dementia. Secondary endpoints were Neuropsychological Test Battery (NTB) composite, Disability Assessment in Dementia (DAD), and Geriatric Depression Scale (GDS) scores. Exploratory outcomes were NTB component, CDR, and MMSE scores. Biomarkers included MRI-derived whole-brain, hippocampus, and entorhinal cortex volumes.
Two hundred ten patients from 15 sites in Austria, Germany, and Israel were randomly allocated to placebo (107 patients) or ladostigil (103 patients). After 36 months, 21 of 103 patients on placebo and 14 of 99 patients receiving ladostigil progressed to Alzheimer disease (log-rank test = 0.162). There were no significant effects on the NTB composite, DAD, or GDS score. Whole-brain and hippocampus volumes decreased more in the placebo than in the ladostigil group (whole brain, = 0.025, Cohen d = 0.43; hippocampus, = 0.043, d = 0.43). Serious adverse events were reported by 28 of 107 patients treated with placebo and 26 of 103 with ladostigil.
Ladostigil was safe and well tolerated but did not delay progression to dementia. Its association with reduced brain and hippocampus volume loss suggests a potential effect on atrophy.
NCT01429623.
This study provides Class II evidence that for patients with MCI and medial temporal lobe atrophy, ladostigil did not significantly decrease the risk of the development of Alzheimer disease.
拉多替吉降低了衰老大鼠的氧化应激和小胶质细胞活化。我们评估了其在患有轻度认知障碍（MCI）和内侧颞叶萎缩的患者中进行的为期 3 年、随机、双盲、安慰剂对照的 2 期临床试验中的安全性和潜在疗效。
将 55 至 85 岁的 MCI 患者，临床痴呆评定量表（CDR）评分为 0.5，简易精神状态检查（MMSE）评分＞24，韦氏记忆量表修订版言语配对联想测验 I 评分≤18，以及内侧颞叶萎缩量表评分＞1，按 ε4 基因型分层，并随机分配（1:1）接受拉多替吉 10mg/d 或安慰剂。主要结局是安全性和阿尔茨海默病痴呆的发病。次要终点是神经心理测试电池（NTB）复合评分、痴呆残疾评估（DAD）和老年抑郁量表（GDS）评分。探索性结局是 NTB 成分、CDR 和 MMSE 评分。生物标志物包括 MRI 衍生的全脑、海马和内嗅皮层体积。
来自奥地利、德国和以色列的 15 个地点的 210 名患者被随机分配至安慰剂（107 名患者）或拉多替吉（103 名患者）组。36 个月后，安慰剂组的 103 名患者中有 21 名和接受拉多替吉的 99 名患者中有 14 名进展为阿尔茨海默病（对数秩检验 = 0.162）。NTB 复合评分、DAD 或 GDS 评分均无显著影响。安慰剂组的全脑和海马体积较拉多替吉组下降更明显（全脑， = 0.025，d = 0.43；海马， = 0.043，d = 0.43）。接受安慰剂治疗的 107 名患者中有 28 名和接受拉多替吉治疗的 103 名患者中有 26 名报告了严重不良事件。
拉多替吉安全且耐受良好，但不能延缓痴呆进展。其与脑和海马体积丢失减少相关，表明其对萎缩有潜在影响。
NCT01429623。
这项研究提供了 II 级证据，表明对于 MCI 和内侧颞叶萎缩的患者，拉多替吉不能显著降低阿尔茨海默病发展的风险。
