title: A multi-center screening trial of rasagiline in patients with amyotrophic lateral sclerosis: Possible mitochondrial biomarker target engagement.
abstract: Rasagiline, a monoamine oxidase B inhibitor, slowed disease progression in the SOD1 mouse, and in a case series of patients with amyotrophic lateral sclerosis (ALS). Here we determine whether rasagiline is safe and effective in ALS compared to historical placebo controls, and whether it alters mitochondrial biomarkers. We performed a prospective open-label, multicenter screening trial of 36 ALS patients treated with 2 mg oral rasagiline daily for 12 months. Outcomes included the slope of deterioration of the revised ALS Functional Rating Scale (ALSFRS-R), adverse event monitoring, time to treatment failure, and exploratory biomarkers. Participants experienced no serious drug-related adverse events, and the most common adverse event was nausea (11.1%). Rasagiline did not improve the rate of decline in the ALSFRS-R; however, differences in symptom duration compared to historical placebo controls differentially affected ALSFRS-R slope estimates. Rasagiline changed biomarkers over 12 months, such that the mitochondrial membrane potential increased (JC-1 red/green fluorescent ratio 1.92, p = 0.0001) and apoptosis markers decreased (Bcl-2/Bax ratio 0.24, p < 0.0001). In conclusion, engagement of exploratory biomarkers and questions about comparability of baseline characteristics lead us to recommend a further placebo-controlled trial.
authors.affiliation: a University of Kansas Medical Center , Kansas.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Macchi
authors.affiliation: a University of Kansas Medical Center , Kansas.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Wang
authors.affiliation: b California Pacific Medical Center , San Francisco , California.
authors.forename: Dan
authors.initials: D
authors.lastname: Moore
authors.affiliation: b California Pacific Medical Center , San Francisco , California.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Katz
authors.affiliation: c Phoenix Neurological Associates , Phoenix , Arizona , Kansas City , Kansas.
authors.forename: David
authors.initials: D
authors.lastname: Saperstein
authors.affiliation: d University of Minnesota , Minneapolis , Minnesota.
authors.forename: David
authors.initials: D
authors.lastname: Walk
authors.affiliation: e The Methodist Hospital , Houston , Texas.
authors.forename: Ericka
authors.initials: E
authors.lastname: Simpson
authors.affiliation: f McGill University , Montreal , Quebec.
authors.forename: Angela
authors.initials: A
authors.lastname: Genge
authors.affiliation: g University of Tennessee , Memphis , Tennessee.
authors.forename: Tulio
authors.initials: T
authors.lastname: Bertorini
authors.affiliation: h University of Nebraska , Omaha , Nebraska.
authors.forename: J Americo
authors.initials: JA
authors.lastname: Fernandes
authors.affiliation: i University of Iowa Health Care , Iowa City , Iowa.
authors.forename: Andrea
authors.initials: A
authors.lastname: Swenson
authors.affiliation: j University of Pennsylvania , Philadelphia , Pennsylvania.
authors.forename: Lauren
authors.initials: L
authors.lastname: Elman
authors.affiliation: a University of Kansas Medical Center , Kansas.
authors.forename: Mazen
authors.initials: M
authors.lastname: Dimachkie
authors.affiliation: a University of Kansas Medical Center , Kansas.
authors.forename: Laura
authors.initials: L
authors.lastname: Herbelin
authors.affiliation: a University of Kansas Medical Center , Kansas.
authors.forename: Joann
authors.initials: J
authors.lastname: Miller
authors.affiliation: a University of Kansas Medical Center , Kansas.
authors.forename: Jianghua
authors.initials: J
authors.lastname: Lu
authors.affiliation: a University of Kansas Medical Center , Kansas.
authors.forename: Heather
authors.initials: H
authors.lastname: Wilkins
authors.affiliation: a University of Kansas Medical Center , Kansas.
authors.forename: Russell H
authors.initials: RH
authors.lastname: Swerdlow
authors.affiliation: a University of Kansas Medical Center , Kansas.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Statland
authors.affiliation: a University of Kansas Medical Center , Kansas.
authors.forename: Richard
authors.initials: R
authors.lastname: Barohn
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D017209:Apoptosis / Q000187:drug effects; D005260:Female; D006801:Humans; D007189:Indans / Q000627:therapeutic use*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D013997:Time Factors; D016896:Treatment Outcome; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D007189:Indans; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C031967:rasagiline
keywords: Biomarker; apoptosis; clinical trials; mitochondria; rasagiline
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