Pub Date : 2024-01-24DOI: 10.1016/s1474-4422(23)00454-4
Ralf Reilmann, Karen E Anderson, Andrew Feigin, Sarah J Tabrizi, Blair R Leavitt, Julie C Stout, Paola Piccini, Robin Schubert, Pippa Loupe, Anna Wickenberg, Beth Borowsky, Gail Rynkowski, Rita Volkinshtein, Thomas Li, Juha-Matti Savola, Michael Hayden, Mark Forrest Gordon
Background
Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of Huntington's disease. Studies with laquinimod in transgenic rodent models of Huntington's disease suggested improvements in motor function, reduction of brain volume loss, and prolonged survival. We aimed to evaluate the safety and efficacy of laquinimod in improving motor function and reducing caudate volume loss in patients with Huntington's disease.
Methods
LEGATO-HD was a multicentre, double-blind, placebo-controlled, phase 2 study done at 48 sites across ten countries (Canada, Czech Republic, Germany, Italy, Netherlands, Portugal, Russia, Spain, UK, and USA). Patients aged 21–55 years with a cytosine-adenosine-guanine (CAG) repeat length of between 36 and 49 who had symptomatic Huntington's disease with a Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) of higher than 5 and a Total Functional Capacity score of 8 or higher were randomly assigned (1:1:1:1) by centralised interactive response technology to laquinimod 0·5 mg, 1·0 mg, or 1·5 mg, or to matching placebo, administered orally once daily over 52 weeks; people involved in the randomisation had no other role in the study. Participants, investigators, and study personnel were masked to treatment assignment. The 1·5 mg group was discontinued before recruitment was finished because of cardiovascular safety concerns in multiple sclerosis studies. The primary endpoint was change from baseline in the UHDRS-TMS and the secondary endpoint was percent change in caudate volume, both comparing the 1·0 mg group with the placebo group at week 52. Primary and secondary endpoints were assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug and had at least one post-baseline UHDRS-TMS assessment). Safety measures included adverse event frequency and severity, and clinical and laboratory examinations, and were assessed in the safety analysis set (ie, all randomised patients who received at least one dose of study drug). This trial is registered with ClinicalTrials.gov, NCT02215616, and EudraCT, 2014–000418–75, and is now complete.
Findings
Between Oct 28, 2014, and June 19, 2018, 352 adults with Huntington's disease (179 [51%] men and 173 [49%] women; mean age 43·9 [SD 7·6] years and 340 [97%] White) were randomly assigned: 107 to laquinimod 0·5 mg, 107 to laquinimod 1·0 mg, 3
背景Laquinimod能调节被认为与亨廷顿病病理有关的中枢神经系统炎症通路。在亨廷顿病转基因啮齿动物模型中使用拉奎尼莫德的研究表明,该药可改善运动功能、减少脑容量损失并延长存活时间。方法LEGATO-HD是一项多中心、双盲、安慰剂对照的2期研究,在10个国家(加拿大、捷克共和国、德国、意大利、荷兰、葡萄牙、俄罗斯、西班牙、英国和美国)的48个地点进行。年龄在 21-55 岁之间、胞嘧啶-腺苷-鸟嘌呤 (CAG) 重复长度在 36-49 之间、有症状且统一亨廷顿氏病评定量表-总运动评分 (UHDRS-TMS) 高于 5 分、总功能能力评分为 8 分或更高的亨廷顿氏病患者被随机分配(1:1:1:1):参与随机分配的人员在研究中没有其他角色。参与者、调查人员和研究人员均被蒙蔽,不知道治疗分配。由于在多发性硬化症研究中存在心血管安全性问题,1-5 毫克组在招募结束前就终止了。主要终点是 UHDRS-TMS 与基线相比的变化,次要终点是尾状体体积变化的百分比,两者均在第 52 周将 1-0 毫克组与安慰剂组进行比较。主要和次要终点均在完整分析集中进行评估(即所有接受了至少一剂研究药物且至少进行了一次基线后 UHDRS-TMS 评估的随机患者)。安全性指标包括不良事件发生频率和严重程度、临床和实验室检查,并在安全性分析集中进行评估(即接受至少一剂研究药物的所有随机患者)。该试验已在ClinicalTrials.gov、NCT02215616和EudraCT、2014-000418-75上注册,现已完成。研究结果在2014年10月28日至2018年6月19日期间,352名亨廷顿氏症成人患者(179名[51%]男性,173名[49%]女性;平均年龄43-9岁[SD 7-6岁],340名[97%]白人)被随机分配:107人接受拉喹莫德0-5毫克治疗,107人接受拉喹莫德1-0毫克治疗,30人接受拉喹莫德1-5毫克治疗,108人接受匹配安慰剂治疗。第52周时,拉喹莫德1-0毫克组UHDRS-TMS与基线相比的最小二乘法平均变化为1-98(SE 0-83),安慰剂组为1-2(0-82)(最小二乘法平均差为0-78 [95% CI -1-42 to 2-98],P=0-4853)。1-0毫克组尾状体体积的最小平方均值变化为3-10%(SE 0-38),安慰剂组为4-86%(0-38)(最小平方均值差-1-76% [95% CI -2-67 to -0-85];P=0-0002)。拉喹莫德耐受性良好,没有新的安全性发现。8名服用安慰剂的患者(7%)、7名服用拉奎莫德0-5毫克的患者(7%)、5名服用拉奎莫德1-0毫克的患者(5%)和1名服用拉奎莫德1-5毫克的患者(3%)报告了严重不良事件。安慰剂组有1例死亡,与治疗无关。在所有拉奎莫德剂量组(0-5毫克、1-0毫克和1-5毫克)中,最常见的不良反应是头痛(38[16%])、腹泻(24[10%])、跌倒(18[7%])、鼻咽炎(20[8%])、流感(15[6%])、呕吐(13[5%])、关节痛(11[5%])、烦躁(10[4%])、疲劳(8[3%])和失眠(8[3%])。解读Laquinimod对UHDRS-TMS评估的运动症状没有显着影响,但与安慰剂相比,在第52周时可显着减少尾状体容积损失。亨廷顿氏病是一种慢性缓慢进展性疾病,本研究并未涉及拉奎尼莫德治疗时间更长是否会在临床评估中产生可检测到的有意义的变化。
{"title":"Safety and efficacy of laquinimod for Huntington's disease (LEGATO-HD): a multicentre, randomised, double-blind, placebo-controlled, phase 2 study","authors":"Ralf Reilmann, Karen E Anderson, Andrew Feigin, Sarah J Tabrizi, Blair R Leavitt, Julie C Stout, Paola Piccini, Robin Schubert, Pippa Loupe, Anna Wickenberg, Beth Borowsky, Gail Rynkowski, Rita Volkinshtein, Thomas Li, Juha-Matti Savola, Michael Hayden, Mark Forrest Gordon","doi":"10.1016/s1474-4422(23)00454-4","DOIUrl":"https://doi.org/10.1016/s1474-4422(23)00454-4","url":null,"abstract":"<h3>Background</h3><p><span><span>Laquinimod modulates CNS inflammatory pathways thought to be involved in the pathology of </span>Huntington's disease. Studies with laquinimod in transgenic rodent models of Huntington's disease suggested improvements in motor function, reduction of brain volume loss, and prolonged survival. We aimed to evaluate the safety and efficacy of laquinimod in improving motor function and reducing caudate volume loss </span>in patients with Huntington's disease.</p><h3>Methods</h3><p><span><span><span>LEGATO-HD was a multicentre, double-blind, placebo-controlled, phase 2 study done at 48 sites across ten countries (Canada, Czech Republic, Germany, Italy, Netherlands, Portugal, Russia, Spain, UK, and USA). Patients aged 21–55 years with a cytosine-adenosine-guanine (CAG) repeat length of between 36 and 49 who had symptomatic Huntington's disease with a Unified Huntington's Disease Rating Scale-Total Motor Score (UHDRS-TMS) of higher than 5 and a Total Functional Capacity score of 8 or higher were randomly assigned (1:1:1:1) by centralised interactive response technology to laquinimod 0·5 mg, 1·0 mg, or 1·5 mg, or to matching placebo, administered orally once daily over 52 weeks; people involved in the randomisation had no other role in the study. Participants, investigators, and study personnel were masked to </span>treatment<span> assignment. The 1·5 mg group was discontinued before recruitment was finished because of cardiovascular safety concerns in multiple sclerosis studies. The primary endpoint was change from baseline in the UHDRS-TMS and the secondary endpoint was percent change in caudate volume, both comparing the 1·0 mg group with the placebo group at week 52. Primary and secondary endpoints were assessed in the full analysis set (ie, all randomised patients who received at least one dose of study </span></span>drug and had at least one post-baseline UHDRS-TMS assessment). Safety measures included adverse event frequency and severity, and clinical and laboratory examinations, and were assessed in the safety analysis set (ie, all randomised patients who received at least one dose of study drug). This trial is registered with </span><span>ClinicalTrials.gov</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"8px\" viewbox=\"0 0 8 8\" width=\"8px\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg>, <span>NCT02215616</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"8px\" viewbox=\"0 0 8 8\" width=\"8px\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg>, and EudraCT, 2014–000418–75, and is now complete.</p><h3>Findings</h3><p>Between Oct 28, 2014, and June 19, 2018, 352 adults with Huntington's disease (179 [51%] men and 173 [49%] women; mean age 43·9 [SD 7·6] years and 340 [97%] White) were randomly assigned: 107 to laquinimod 0·5 mg, 107 to laquinimod 1·0 mg, 3","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139568602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-24DOI: 10.1016/s1474-4422(24)00001-2
Tiago A Mestre
Abstract not available
无摘要
{"title":"Laquinimod, Huntington's disease, and disease modification","authors":"Tiago A Mestre","doi":"10.1016/s1474-4422(24)00001-2","DOIUrl":"https://doi.org/10.1016/s1474-4422(24)00001-2","url":null,"abstract":"Abstract not available","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"158 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139550594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-24DOI: 10.1016/s1474-4422(24)00031-0
Harris A Eyre, William Hynes, Rym Ayadi, Facundo Manes, Pawel Swieboda
Abstract not available
无摘要
{"title":"Brain capital is crucial for global sustainable development","authors":"Harris A Eyre, William Hynes, Rym Ayadi, Facundo Manes, Pawel Swieboda","doi":"10.1016/s1474-4422(24)00031-0","DOIUrl":"https://doi.org/10.1016/s1474-4422(24)00031-0","url":null,"abstract":"Abstract not available","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139568534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-22DOI: 10.1016/s1474-4422(23)00508-2
Eric M Reiman, Jeffrey L Cummings, Jessica B Langbaum, Soeren Mattke, Robert C Alexander
Abstract not available
无摘要
{"title":"A chance to prevent Alzheimer's disease sooner than you think","authors":"Eric M Reiman, Jeffrey L Cummings, Jessica B Langbaum, Soeren Mattke, Robert C Alexander","doi":"10.1016/s1474-4422(23)00508-2","DOIUrl":"https://doi.org/10.1016/s1474-4422(23)00508-2","url":null,"abstract":"Abstract not available","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"71 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139522967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-22DOI: 10.1016/s1474-4422(23)00460-x
Aravind Ganesh
Abstract not available
无摘要
{"title":"Platelet glycoprotein VI inhibition: a promising therapeutic avenue in acute ischaemic stroke","authors":"Aravind Ganesh","doi":"10.1016/s1474-4422(23)00460-x","DOIUrl":"https://doi.org/10.1016/s1474-4422(23)00460-x","url":null,"abstract":"Abstract not available","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139522869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-22DOI: 10.1016/s1474-4422(23)00456-8
Clifford R Jack
Abstract not available
无摘要
{"title":"Criteria for a biological definition of neuronal α-synuclein disease—a major conceptual step forward","authors":"Clifford R Jack","doi":"10.1016/s1474-4422(23)00456-8","DOIUrl":"https://doi.org/10.1016/s1474-4422(23)00456-8","url":null,"abstract":"Abstract not available","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139522983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-22DOI: 10.1016/s1474-4422(23)00501-x
Alexandre Bejanin, Nicolas Villain
Abstract not available
无摘要
{"title":"Posterior cortical atrophy: new insights into treatments and biomarkers for Alzheimer's disease","authors":"Alexandre Bejanin, Nicolas Villain","doi":"10.1016/s1474-4422(23)00501-x","DOIUrl":"https://doi.org/10.1016/s1474-4422(23)00501-x","url":null,"abstract":"Abstract not available","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"71 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139522952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-22DOI: 10.1016/s1474-4422(23)00404-0
Günter U Höglinger, Charles H Adler, Daniela Berg, Christine Klein, Tiago F Outeiro, Werner Poewe, Ronald Postuma, A Jon Stoessl, Anthony E Lang
With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically based classification. Our classification acknowledges the complexity and heterogeneity of the disease by use of a three-component system (SynNeurGe): presence or absence of pathological α-synuclein (S) in tissues or CSF; evidence of underlying neurodegeneration (N) defined by neuroimaging procedures; and documentation of pathogenic gene variants (G) that cause or strongly predispose to Parkinson's disease. These three components are linked to a clinical component (C), defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features. The use of a biological classification will enable advances in both basic and clinical research, and move the field closer to the precision medicine required to develop disease-modifying therapies. We emphasise the initial application of these criteria exclusively for research. We acknowledge its ethical implications, its limitations, and the need for prospective validation in future studies.
{"title":"A biological classification of Parkinson's disease: the SynNeurGe research diagnostic criteria","authors":"Günter U Höglinger, Charles H Adler, Daniela Berg, Christine Klein, Tiago F Outeiro, Werner Poewe, Ronald Postuma, A Jon Stoessl, Anthony E Lang","doi":"10.1016/s1474-4422(23)00404-0","DOIUrl":"https://doi.org/10.1016/s1474-4422(23)00404-0","url":null,"abstract":"<p><span><span>With the hope that disease-modifying treatments could target the molecular basis of </span>Parkinson's disease<span>, even before the onset of symptoms, we propose a biologically based classification. Our classification acknowledges the complexity and heterogeneity of the disease by use of a three-component system (SynNeurGe): presence or absence of pathological α-synuclein (S) in tissues or CSF; evidence of underlying neurodegeneration (N) defined by neuroimaging procedures; and documentation of pathogenic gene variants (G) that cause or strongly predispose to Parkinson's disease. These three components are linked to a clinical component (C), defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features. The use of a biological classification will enable advances in both basic and </span></span>clinical research, and move the field closer to the precision medicine required to develop disease-modifying therapies. We emphasise the initial application of these criteria exclusively for research. We acknowledge its ethical implications, its limitations, and the need for prospective validation in future studies.</p>","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"57 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139522839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-01-22DOI: 10.1016/s1474-4422(23)00499-4
Benzi M Kluger
Abstract not available
无摘要
{"title":"A multipronged approach to advancing palliative care for people with intellectual disabilities – Author's reply","authors":"Benzi M Kluger","doi":"10.1016/s1474-4422(23)00499-4","DOIUrl":"https://doi.org/10.1016/s1474-4422(23)00499-4","url":null,"abstract":"Abstract not available","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"179 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139522881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}