氨溴索作为帕金森病痴呆的一种新型疾病修饰治疗方法：一项单中心、随机、双盲、安慰剂对照试验的方案
Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial.
作者信息
Silveira C R A, MacKinley J, Coleman K, Li Z, Finger E, Bartha R, Morrow S A, Wells J, Borrie M, Tirona R G, Rupar C A, Zou G, Hegele R A, Mahuran D, MacDonald P, Jenkins M E, Jog M, Pasternak S H
机构信息
Cognitive Neurology and Alzheimer's Disease Research Centre, Parkwood Institute - Main Building, Room A230, 550, Wellington Road, London, Ontario, N6G 0A7, Canada.
Lawson Health Research Institute, London, Ontario, Canada.
出版信息
BMC Neurol. 2019 Feb 9;19(1):20. doi: 10.1186/s12883-019-1252-3.
BACKGROUND
Currently there are no disease-modifying treatments for Parkinson's disease dementia (PDD), a condition linked to aggregation of the protein α-synuclein in subcortical and cortical brain areas. One of the leading genetic risk factors for Parkinson's disease is being a carrier in the gene for β-Glucocerebrosidase (GCase; gene name GBA1). Studies in cell culture and animal models have shown that raising the levels of GCase can decrease levels of α-synuclein. Ambroxol is a pharmacological chaperone for GCase and is able to raise the levels of GCase and could therefore be a disease-modifying treatment for PDD. The aims of this trial are to determine if Ambroxol is safe and well-tolerated by individuals with PDD and if Ambroxol affects cognitive, biochemical, and neuroimaging measures.
METHODS
This is a phase II, single-centre, double-blind, randomized placebo-controlled trial involving 75 individuals with mild to moderate PDD. Participants will be randomized into Ambroxol high-dose (1050 mg/day), low-dose (525 mg/day), or placebo treatment arms. Assessments will be undertaken at baseline, 6-months, and 12-months follow up times. Primary outcome measures will be the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-Cog) and the ADCS Clinician's Global Impression of Change (CGIC). Secondary measures will include the Parkinson's disease Cognitive Rating Scale, Clinical Dementia Rating, Trail Making Test, Stroop Test, Unified Parkinson's disease Rating Scale, Purdue Pegboard, Timed Up and Go, and gait kinematics. Markers of neurodegeneration will include MRI and CSF measures. Pharmacokinetics and pharmacodynamics of Ambroxol will be examined through plasma levels during dose titration phase and evaluation of GCase activity in lymphocytes.
DISCUSSION
If found effective and safe, Ambroxol will be one of the first disease-modifying treatments for PDD.
TRIAL REGISTRATION
ClinicalTrials.gov NCT02914366, 26 Sep 2016/retrospectively registered.
背景
目前尚无针对帕金森病痴呆（PDD）的疾病修饰治疗方法，PDD与蛋白质α-突触核蛋白在皮层下和皮层脑区的聚集有关。帕金森病的主要遗传风险因素之一是成为β-葡萄糖脑苷脂酶（GCase；基因名GBA1）基因的携带者。细胞培养和动物模型研究表明，提高GCase水平可降低α-突触核蛋白水平。氨溴索是GCase的一种药理伴侣，能够提高GCase水平，因此可能是一种针对PDD的疾病修饰治疗方法。本试验的目的是确定氨溴索对PDD患者是否安全且耐受性良好，以及氨溴索是否会影响认知、生化和神经影像学指标。
方法
这是一项II期、单中心、双盲、随机安慰剂对照试验，涉及75例轻度至中度PDD患者。参与者将被随机分为高剂量（1050毫克/天）、低剂量（525毫克/天）氨溴索治疗组或安慰剂治疗组。在基线、6个月和12个月随访时进行评估。主要结局指标将是阿尔茨海默病评估量表-认知分量表（ADAS-Cog）和ADCS临床医生总体变化印象（CGIC）。次要指标将包括帕金森病认知评定量表、临床痴呆评定量表、连线测验、斯特鲁普测验、统一帕金森病评定量表、普渡钉板测验、定时起立行走测试和步态运动学。神经退行性变的标志物将包括MRI和脑脊液指标。将在剂量滴定阶段通过血浆水平检查氨溴索的药代动力学和药效学，并评估淋巴细胞中的GCase活性。
讨论
如果氨溴索被证明有效且安全，它将成为首批针对PDD的疾病修饰治疗方法之一。
试验注册
ClinicalTrials.gov NCT02914366，2016年9月26日/追溯注册。
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