THERAPEUTIC TRIALS OF X-LINKED ALD: PHASE III; LORENZO*

描述（由申请人提供）： 研究者建议进行一项双盲、安慰剂对照的研究，以探讨LO治疗成人型X-连锁肾上腺脑白质营养不良（X-ALD）的疗效。 AMN进展缓慢。 它是一种累及脊髓长束的远端轴突病，不同于最常影响男孩和青少年的快速进行性炎症性脑疾病。 AMN分为两种形式。 病理仅限于脊髓和外周神经的“纯型”，以及存在炎性脑受累的额外证据的AMN脑表型。 所有形式的X-ALD都与血浆和组织中极长链脂肪酸（VLCFA）的异常积累有关。口服LO使X-ALD患者的血浆VLCFA水平在四周内恢复正常，并且在过去14年中进行了各种治疗试验。 虽然先前在患有大脑形式的X-ALD的患者中进行的LO治疗试验令人失望，但最近的研究提供了相当多的证据，表明它对两种类型的X-ALD有益：1）提示性证据表明它将纯AMN的进展减缓了50%，2）当给予神经正常且具有正常脑磁共振成像（MRI）的男孩时，具有预防作用。 以前的研究都是单队列研究。 研究人员现在提出了第一个安慰剂对照试验。 这项为期三年的研究将涉及120名男性和120名女性AMN患者。 该研究将由Westat协调。 将比较LO组和安慰剂组的进展率。 Kurtzke扩展残疾状态量表（EDSS）评分将是主要结局指标。 还将使用各种次要结局指标。 现在认识到，50%的杂合子发展为纯AMN，这可能导致相当大的残疾。 这是第一个涉及X-ALD杂合子女性的治疗研究。

DESCRIPTION (provided by applicant): The investigators propose to conduct a double-masked, placebo-controlled study of LO therapy in AMN, the adult form of X-Iinked adrenoleukodystrophy (X-ALD). AMN is slowly progressive. It is a distal axonopathy that involves the long tracts of the spinal cord and differs from the rapidly progressive inflammatory cerebral forms that most commonly affect boys and adolescents. AMN is subdivided into two forms. The "pure form" in which pathology is confined to spinal cord and peripheral nerve, and the AMN cerebral phenotype in which there is additional evidence of inflammatory cerebral involvement. All forms of X-ALD are associated with the abnormal accumulation of very long chain fatty acids (VLCFA) in plasma and tissues. The oral administration of LO normalizes plasma VLCFA levels in X-ALD patients within four weeks, and various therapeutic trials have been conducted during the last 14 years. While previous therapeutic trials of LO in patients with the cerebraI forms of X-ALD were disappointing, recent studies provide considerable evidence that it is beneficial in two types of X-ALD: 1) suggestive evidence that it slows progression of pure AMN by 50% and 2) preventive effect when administered to boys who are neurologically normal and have normal brain magnetic resonance imaging (MRI). Previous studies have been single cohort. The investigators now propose the first placebo-controlled trial. It will be a three-year study that will involve 120 men and 120 women with AMN. The study will be coordinated by Westat. The rate of progression will be compared in the LO and placebo groups. The Kurtzke Expanded Disability Status Scale (EDSS) score will be the primary outcome measure. A variety of secondary outcome measures will also be used. It is now recognized that 50% of heterozygous develop pure AMN which may lead to considerable disability. This is the first therapeutic study that also involves women heterozygous for X-ALD.