title: A0001 in Friedreich ataxia: biochemical characterization and effects in a clinical trial.
abstract: This study tested the ability of A0001 (α-tocopheryl quinone; EPI-A0001), a potent antioxidant, to improve in vitro measures, glucose metabolism, and neurological function in Friedreich ataxia. We used an in vitro study of protection from cell toxicity followed by a double-blind, randomized, placebo-controlled trial of 2 doses of A0001 in 31 adults with Friedreich ataxia. The primary clinical trial outcome was the Disposition Index, a measure of diabetic tendency, from a frequently sampled intravenous glucose tolerance test, evaluated 4 weeks into therapy. Secondary neurologic measures included the Friedreich Ataxia Rating Scale. A0001 potently inhibited cell death in Friedreich ataxia models in vitro. For the clinical trial, mean guanine-adenine-adenine repeat length was 699, and mean age was 31 years. Four weeks after treatment initiation, differences in changes in the Disposition Index between subjects treated with A0001 and placebo were not statistically significant. In contrast, a dose-dependent improvement in the Friedreich Ataxia Rating Scale score was observed. Patients on placebo improved 2.0 rating scale points, whereas patients on low-dose A0001 improved by 4.9 points (P = .04) and patients on a high dose improved by 6.1 points (P < .01). Although A0001 did not alter the Disposition Index, it caused a dose-dependent improvement in neurologic function, as measured by the Friedreich Ataxia Rating Scale. Longer studies will assess the reproducibility and persistence of neurologic benefit.
authors: Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, USA. lynchd@mail.med.upenn.edu
authors: David R
authors: DR
authors: Lynch
authors: Steven M
authors: SM
authors: Willi
authors: Robert B
authors: RB
authors: Wilson
authors: M Grazia
authors: MG
authors: Cotticelli
authors: Karlla W
authors: KW
authors: Brigatti
authors: Eric C
authors: EC
authors: Deutsch
authors: Olena
authors: O
authors: Kucheruk
authors: William
authors: W
authors: Shrader
authors: Patrice
authors: P
authors: Rioux
authors: Guy
authors: G
authors: Miller
authors: Amale
authors: A
authors: Hawi
authors: Thomas
authors: T
authors: Sciascia
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005621:Friedreich Ataxia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D033862:Iron-Binding Proteins / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D017354:Point Mutation; D018401:Sample Size; D016896:Treatment Outcome; D014810:Vitamin E / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D055815:Young Adult; D000096923:Frataxin
chemical_list: D000975:Antioxidants; D015415:Biomarkers; D005947:Glucose; D033862:Iron-Binding Proteins; D014810:Vitamin E; D000096923:Frataxin; C002421:tocopherylquinone