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

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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.