Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial.
Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial.
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DOI：
10.1016/s0140-6736(16)31275-2
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发表时间：
2016-12-10
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通讯作者：
Wischik CM
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作者：
Gauthier S;Feldman HH;Schneider LS;Wilcock GK;Frisoni GB;Hardlund JH;Moebius HJ;Bentham P;Kook KA;Wischik DJ;Schelter BO;Davis CS;Staff RT;Bracoud L;Shamsi K;Storey JM;Harrington CR;Wischik CM
Leuco-methylthioninium bis（hydromethanesulfonate; LMTM）是methylthioninium部分的稳定还原形式，在体外和转基因小鼠模型中作为tau蛋白聚集的选择性抑制剂。亚甲蓝氯化物先前已显示出作为单一疗法治疗阿尔茨海默病患者的潜在疗效。我们的目的是确定LMTM是否安全有效地改变轻度至中度阿尔茨海默病患者的疾病进展。我们在欧洲、北美、亚洲和俄罗斯16个国家的115个学术中心和私人研究诊所进行了一项为期15个月的随机、对照、双盲、平行组试验，患者年龄小于90岁，患有轻度至中度阿尔茨海默病。允许合并使用其他药物治疗阿尔茨海默病的患者入选，因为我们认为不允许其入选是不可行的;但是，排除了使用带有高铁血红蛋白血症警告的药物的患者，因为高剂量的氧化形式的亚甲蓝已被证明会诱发这种疾病。我们将受试者（3：3：4）随机分配至75 mg LMTM每日两次、125 mg LMTM每日两次或对照组（4 mg LMTM每日两次，以维持对尿液或粪便变色的盲态），以口服片剂形式给药。我们使用交互式网络应答系统进行随机化，使用600个长度为10的区组，并按疾病严重程度、全球地区、是否同时使用阿尔茨海默病标签药物和研究中心PET能力对患者进行分层。参与者、他们的研究伙伴（通常是护理人员）和所有评估人员在整个研究期间对治疗分配设盲。共同主要结局为改良意向治疗人群中阿尔茨海默病评估量表-认知子量表（ADAS-Cog）和阿尔茨海默病合作研究-日常生活活动量表（ADCS-ADL）量表在第65周较基线评估的进展。本试验已在Clinicaltrials.gov（NCT 01689246）和欧盟临床试验注册中心（2012-002866-11）注册。在2013年1月29日至2014年6月26日期间，我们招募并随机分配了891名参与者进行治疗（357名为对照组，268至75 mg LMTM每日两次，266至125 mg LMTM每日两次）。预先规定的主要分析未显示在共同主要结局的任一检测剂量下的任何治疗获益（ADAS-Cog评分与对照组相比的变化[n=354，6.32，95% CI 5.31 - 7.34]：75 mg LMTM每日2次[n=257] -0 statist 02，-1 statist 60至1·56，p=0·9834，125 mg LMTM每日2次[n=250] -0 statist 43，-2 statist 06至1·20，p=0·9323;与对照组相比，ADCS-ADL评分的变化[-8统计22，95%CI-9统计63至-6统计82]：75 mg LMTM每日两次-0统计93，-3统计12至1·26，p=0·8659; 125 mg LMTM每日两次-0统计34，-2统计61至1·93，p=0·9479）。胃肠道和泌尿系统影响是高剂量LMTM最常见的不良事件，也是最常见的停药原因。血红蛋白浓度的非临床显著剂量依赖性降低是最常见的实验室异常。淀粉样蛋白相关成像异常在不到1%（8/885）的参与者中观察到。这项研究的主要分析是负面的，结果并不表明LMTM作为轻度至中度阿尔茨海默病患者的附加治疗的益处。最近完成的一项为期18个月的轻度阿尔茨海默病患者试验的结果将很快公布。TauRx治疗公司。
Leuco-methylthioninium bis(hydromethanesulfonate; LMTM), a stable reduced form of the methylthioninium moiety, acts as a selective inhibitor of tau protein aggregation both in vitro and in transgenic mouse models. Methylthioninium chloride has previously shown potential efficacy as monotherapy in patients with Alzheimer’s disease. We aimed to determine whether LMTM was safe and effective in modifying disease progression in patients with mild to moderate Alzheimer’s disease. We did a 15-month, randomised, controlled double-blind, parallel-group trial at 115 academic centres and private research clinics in 16 countries in Europe, North America, Asia, and Russia with patients younger than 90 years with mild to moderate Alzheimer’s disease. Patients concomitantly using other medicines for Alzheimer’s disease were permitted to be included because we considered it infeasible not to allow their inclusion; however, patients using medicines carrying warnings of methaemoglobinaemia were excluded because the oxidised form of methylthioninium in high doses has been shown to induce this condition. We randomly assigned participants (3:3:4) to 75 mg LMTM twice a day, 125 mg LMTM twice a day, or control (4 mg LMTM twice a day to maintain blinding with respect to urine or faecal discolouration) administered as oral tablets. We did the randomisation with an interactive web response system using 600 blocks of length ten, and stratified patients by severity of disease, global region, whether they were concomitantly using Alzheimer’s disease-labelled medications, and site PET capability. Participants, their study partners (generally carers), and all assessors were masked to treatment assignment throughout the study. The coprimary outcomes were progression on the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and the Alzheimer’s Disease Co-operative Study–Activities of Daily Living Inventory (ADCS-ADL) scales from baseline assessed at week 65 in the modified intention-to-treat population. This trial is registered with Clinicaltrials.gov (NCT01689246) and the European Union Clinical Trials Registry (2012-002866-11). Between Jan 29, 2013, and June 26, 2014, we recruited and randomly assigned 891 participants to treatment (357 to control, 268 to 75 mg LMTM twice a day, and 266 to 125 mg LMTM twice a day). The prespecified primary analyses did not show any treatment benefit at either of the doses tested for the coprimary outcomes (change in ADAS-Cog score compared with control [n=354, 6·32, 95% CI 5·31–7·34]: 75 mg LMTM twice a day [n=257] –0·02, –1·60 to 1·56, p=0·9834, 125 mg LMTM twice a day [n=250] –0·43, –2·06 to 1·20, p=0·9323; change in ADCS-ADL score compared with control [–8·22, 95% CI –9·63 to –6·82]: 75 mg LMTM twice a day –0·93, –3·12 to 1·26, p=0·8659; 125 mg LMTM twice a day –0·34, –2·61 to 1·93, p=0·9479). Gastrointestinal and urinary effects were the most common adverse events with both high doses of LMTM, and the most common causes for discontinuation. Non-clinically significant dose-dependent reductions in haemoglobin concentrations were the most common laboratory abnormality. Amyloid-related imaging abnormalities were noted in less than 1% (8/885) of participants. The primary analysis for this study was negative, and the results do not suggest benefit of LMTM as an add-on treatment for patients with mild to moderate Alzheimer’s disease. Findings from a recently completed 18-month trial of patients with mild Alzheimer’s disease will be reported soon. TauRx Therapeutics.