Abstract：
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.
RESULTS: 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, 30 to laquinimod 1·5 mg, and 108 to matching placebo. Least squares mean change from baseline in UHDRS-TMS at week 52 was 1·98 (SE 0·83) in the laquinimod 1·0 mg group and 1·2 (0·82) in the placebo group (least squares mean difference 0·78 [95% CI -1·42 to 2·98], p=0·4853). Least squares mean change in caudate volume was 3·10% (SE 0·38) in the 1·0 mg group and 4·86% (0·38) in the placebo group (least squares mean difference -1·76% [95% CI -2·67 to -0·85]; p=0·0002). Laquinimod was well tolerated and there were no new safety findings. Serious adverse events were reported by eight (7%) patients on placebo, seven (7%) on laquinimod 0·5 mg, five (5%) on laquinimod 1·0 mg, and one (3%) on laquinimod 1·5 mg. There was one death, which occurred in the placebo group and was unrelated to treatment. The most frequent adverse events in all laquinimod dosed groups (0·5 mg, 1·0 mg, and 1·5 mg) were headache (38 [16%]), diarrhoea (24 [10%]), fall (18 [7%]), nasopharyngitis (20 [8%]), influenza (15 [6%]), vomiting (13 [5%]), arthralgia (11 [5%]), irritability (ten [4%]), fatigue (eight [3%]), and insomnia (eight [3%]).
CONCLUSIONS: Laquinimod did not show a significant effect on motor symptoms assessed by the UHDRS-TMS, but significantly reduced caudate volume loss compared with placebo at week 52. Huntington\'s disease has a chronic and slowly progressive course, and this study does not address whether a longer duration of laquinimod treatment could have produced detectable and meaningful changes in the clinical assessments.
BACKGROUND: Teva Pharmaceutical Industries.
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.
RESULTS: 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, 30 to laquinimod 1·5 mg, and 108 to matching placebo. Least squares mean change from baseline in UHDRS-TMS at week 52 was 1·98 (SE 0·83) in the laquinimod 1·0 mg group and 1·2 (0·82) in the placebo group (least squares mean difference 0·78 [95% CI -1·42 to 2·98], p=0·4853). Least squares mean change in caudate volume was 3·10% (SE 0·38) in the 1·0 mg group and 4·86% (0·38) in the placebo group (least squares mean difference -1·76% [95% CI -2·67 to -0·85]; p=0·0002). Laquinimod was well tolerated and there were no new safety findings. Serious adverse events were reported by eight (7%) patients on placebo, seven (7%) on laquinimod 0·5 mg, five (5%) on laquinimod 1·0 mg, and one (3%) on laquinimod 1·5 mg. There was one death, which occurred in the placebo group and was unrelated to treatment. The most frequent adverse events in all laquinimod dosed groups (0·5 mg, 1·0 mg, and 1·5 mg) were headache (38 [16%]), diarrhoea (24 [10%]), fall (18 [7%]), nasopharyngitis (20 [8%]), influenza (15 [6%]), vomiting (13 [5%]), arthralgia (11 [5%]), irritability (ten [4%]), fatigue (eight [3%]), and insomnia (eight [3%]).
CONCLUSIONS: Laquinimod did not show a significant effect on motor symptoms assessed by the UHDRS-TMS, but significantly reduced caudate volume loss compared with placebo at week 52. Huntington\'s disease has a chronic and slowly progressive course, and this study does not address whether a longer duration of laquinimod treatment could have produced detectable and meaningful changes in the clinical assessments.
BACKGROUND: Teva Pharmaceutical Industries.
摘要：
背景：拉喹莫德调节中枢神经系统炎症通路，被认为与亨廷顿病的病理有关。拉喹莫德在亨廷顿氏病转基因啮齿动物模型中的研究表明运动功能有所改善，减少脑容量损失，和延长生存期。我们旨在评估拉喹莫德在改善亨廷顿病患者运动功能和减少尾状体积损失方面的安全性和有效性。
方法：LEGATO-HD是多中心，双盲,安慰剂对照,在10个国家的48个地点进行的第二阶段研究(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）。21-55岁，胞嘧啶-腺苷-鸟嘌呤（CAG）重复长度在36至49岁之间的患者，有症状的亨廷顿病，统一亨廷顿疾病评定量表-总运动评分（UHDRS-TMS）高于5，总功能评分为8或更高，通过集中式交互式反应技术将其随机分配（1：1：1：1：1）给拉喹莫德，5。1·0毫克，或1·5毫克，或者匹配安慰剂，在52周内每天口服一次;参与随机分组的人在研究中没有其他作用。参与者,调查员,和研究人员被掩盖治疗分配。在多发性硬化症研究中，由于心血管安全问题，1·5mg组在招募结束前停止。主要终点是UHDRS-TMS相对于基线的变化，次要终点是尾状体积的百分比变化，两者在第52周比较1·0mg组与安慰剂组。在完整的分析集中评估主要和次要终点(即，所有接受至少一剂研究药物并接受至少一次基线后UHDRS-TMS评估的随机患者).安全措施包括不良事件的频率和严重程度。以及临床和实验室检查，并在安全性分析集中进行了评估(即，所有接受至少一剂研究药物的随机患者)。该试验已在ClinicalTrials.gov注册，NCT02215616和EudraCT,2014-000418-75，现已完成。
结果：在2014年10月28日至2018年6月19日之间，352名患有亨廷顿病的成年人（男性179[51％]和女性173[49％]；平均年龄43·9[SD7·6]岁和340[97％]白人）被随机分配：107至拉喹莫德0·5毫克，107至拉喹莫德1·0毫克，30至拉喹莫德1·5毫克，和108匹配的安慰剂。在第52周时，拉喹莫德1·0mg组为1·98（SE0·83），安慰剂组为1·2（0·82）（最小二乘平均差0·78[95％CI-1·42至2·98]，p=0·4853）。1·0mg组尾状体积的最小二乘均值变化为3·10％（SE0·38），安慰剂组为4·86％（0·38）（最小二乘均值-1·76％[95％CI-2·67至-0·85]；p=0·0002）。拉喹莫德的耐受性良好，没有新的安全性发现。8名（7%）服用安慰剂的患者报告了严重的不良事件，七（7%）在拉喹莫德0·5毫克，五（5%）对拉喹莫德1·0毫克，和一个（3%）在拉喹莫德1·5毫克。有一次死亡,这发生在安慰剂组，与治疗无关。所有拉喹莫德剂量组中最常见的不良事件（0·5mg，1·0毫克，1·5毫克)是头痛(38[16%])，腹泻（24[10%]），下跌（18[7%]），鼻咽炎（20[8%]），流感（15[6%]），呕吐（13[5%]），关节痛（11[5%]），烦躁(十[4%])，疲劳(八[3%])，失眠（八[3%]）。
结论：拉喹莫德对UHDRS-TMS评估的运动症状没有显着影响，但在第52周，与安慰剂相比，尾状体积损失显著减少。亨廷顿病有一个慢性和缓慢进展的过程，而这项研究没有说明拉喹莫德治疗时间较长是否会在临床评估中产生可检测的有意义的变化.
背景：Teva制药工业。
方法：LEGATO-HD是多中心，双盲,安慰剂对照,在10个国家的48个地点进行的第二阶段研究(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）。21-55岁，胞嘧啶-腺苷-鸟嘌呤（CAG）重复长度在36至49岁之间的患者，有症状的亨廷顿病，统一亨廷顿疾病评定量表-总运动评分（UHDRS-TMS）高于5，总功能评分为8或更高，通过集中式交互式反应技术将其随机分配（1：1：1：1：1）给拉喹莫德，5。1·0毫克，或1·5毫克，或者匹配安慰剂，在52周内每天口服一次;参与随机分组的人在研究中没有其他作用。参与者,调查员,和研究人员被掩盖治疗分配。在多发性硬化症研究中，由于心血管安全问题，1·5mg组在招募结束前停止。主要终点是UHDRS-TMS相对于基线的变化，次要终点是尾状体积的百分比变化，两者在第52周比较1·0mg组与安慰剂组。在完整的分析集中评估主要和次要终点(即，所有接受至少一剂研究药物并接受至少一次基线后UHDRS-TMS评估的随机患者).安全措施包括不良事件的频率和严重程度。以及临床和实验室检查，并在安全性分析集中进行了评估(即，所有接受至少一剂研究药物的随机患者)。该试验已在ClinicalTrials.gov注册，NCT02215616和EudraCT,2014-000418-75，现已完成。
结果：在2014年10月28日至2018年6月19日之间，352名患有亨廷顿病的成年人（男性179[51％]和女性173[49％]；平均年龄43·9[SD7·6]岁和340[97％]白人）被随机分配：107至拉喹莫德0·5毫克，107至拉喹莫德1·0毫克，30至拉喹莫德1·5毫克，和108匹配的安慰剂。在第52周时，拉喹莫德1·0mg组为1·98（SE0·83），安慰剂组为1·2（0·82）（最小二乘平均差0·78[95％CI-1·42至2·98]，p=0·4853）。1·0mg组尾状体积的最小二乘均值变化为3·10％（SE0·38），安慰剂组为4·86％（0·38）（最小二乘均值-1·76％[95％CI-2·67至-0·85]；p=0·0002）。拉喹莫德的耐受性良好，没有新的安全性发现。8名（7%）服用安慰剂的患者报告了严重的不良事件，七（7%）在拉喹莫德0·5毫克，五（5%）对拉喹莫德1·0毫克，和一个（3%）在拉喹莫德1·5毫克。有一次死亡,这发生在安慰剂组，与治疗无关。所有拉喹莫德剂量组中最常见的不良事件（0·5mg，1·0毫克，1·5毫克)是头痛(38[16%])，腹泻（24[10%]），下跌（18[7%]），鼻咽炎（20[8%]），流感（15[6%]），呕吐（13[5%]），关节痛（11[5%]），烦躁(十[4%])，疲劳(八[3%])，失眠（八[3%]）。
结论：拉喹莫德对UHDRS-TMS评估的运动症状没有显着影响，但在第52周，与安慰剂相比，尾状体积损失显著减少。亨廷顿病有一个慢性和缓慢进展的过程，而这项研究没有说明拉喹莫德治疗时间较长是否会在临床评估中产生可检测的有意义的变化.
背景：Teva制药工业。
