title: Flecainide in Amyotrophic Lateral Sclerosis as a Neuroprotective Strategy (FANS): A Randomized Placebo-Controlled Trial.
abstract: BACKGROUND
  Abnormalities in membrane excitability and Na(+) channel function are characteristic of amyotrophic lateral sclerosis (ALS). We aimed to examine the neuroprotective potential, safety and tolerability of the Na(+) channel blocker and membrane stabiliser flecainide in ALS.
  
  
  METHODS
  A double-blind, placebo-controlled, randomised clinical trial of flecainide (200 mg/day) for 32-weeks with a 12-week lead-in phase was conducted in participants with probable or definite ALS recruited from multiple Australian centres (ANZCT Registry number ACTRN12608000338369). Patients were reviewed by a cardiologist to rule out cardiac contraindications. Participants were randomly assigned (1:1) to flecainide or placebo using stratified permuted blocks by a central pharmacy. The primary outcome measure was the slope of decline of the ALS Functional Rating Scale-revised (ALS FRS-r) during the treatment period.
  
  
  RESULTS
  Between March 11, 2008 and July 1, 2010, 67 patients were screened, 54 of whom were randomly assigned to receive flecainide (26 patients) or placebo (28 patients). Four patients in the flecainide group and three patients in the placebo group withdrew from the study. One patient in the flecainide group died during the study, attributed to disease progression. Flecainide was generally well tolerated, with no serious adverse events reported in either group. There was no significant difference in the rate of decline in the primary outcome measure ALS-FRS-r between placebo and flecainide treated patients (Flecainide 0.65 [95% CI 0.49 to 0.98]; Placebo 0.81 [0.49 to 2.12] P = 0.50). However, the rate of decline of the neurophysiological index was significantly reduced in the flecainide group (Flecainide 0.06 [0.01 to 0.11]; Placebo 0.14 [0.09 to 0.19], P = 0.02). Placebo-treated patients demonstrated greater CMAP amplitude reduction during the course of the study in the subset of patients with a reduced baseline CMAP amplitude (Flecainide: - 15 ± 12%; Placebo - 59 ± 12%; P = 0.03). Flecainide-treated patients maintained stabilized peripheral axonal excitability over the study compared to placebo.
  
  
  CONCLUSIONS
  This pilot study indicated that flecainide was safe and potentially biologically effective in ALS. There was evidence that flecainide stabilized peripheral axonal membrane function in ALS. While the study was not powered to detect evidence of benefit of flecainide on ALS-FRS-r decline, further studies may demonstrate clinical efficacy of flecainide in ALS.
authors: Brain and Mind Centre, Sydney Medical School, University of Sydney, Australia.
authors: Susanna B
authors: SB
authors: Park
authors: Western Clinical School, University of Sydney, Australia.
authors: Steve
authors: S
authors: Vucic
authors: Brain and Mind Centre, Sydney Medical School, University of Sydney, Australia.
authors: Benjamin C
authors: BC
authors: Cheah
authors: School of Medical Sciences, University of New South Wales, Australia.
authors: Cindy S-Y
authors: CS
authors: Lin
authors: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Australia.
authors: Adrienne
authors: A
authors: Kirby
authors: National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Australia.
authors: Kristy P
authors: KP
authors: Mann
authors: Brain and Mind Centre, Sydney Medical School, University of Sydney, Australia.
authors: Margie C
authors: MC
authors: Zoing
authors: Brain and Mind Centre, Sydney Medical School, University of Sydney, Australia.
authors: Jennica
authors: J
authors: Winhammar
authors: Brain and Mind Centre, Sydney Medical School, University of Sydney, Australia.
authors: Matthew C
authors: MC
authors: Kiernan
mesh_terms: D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005424:Flecainide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011788:Quality of Life; D016896:Treatment Outcome; D061567:Voltage-Gated Sodium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D018696:Neuroprotective Agents; D061567:Voltage-Gated Sodium Channel Blockers; D005424:Flecainide
keywords: Amyotrophic lateral sclerosis; Flecainide; Neuroprotection; Sodium channel