Flecainide in Amyotrophic Lateral Sclerosis as a Neuroprotective Strategy (FANS): A Randomized Placebo-Controlled Trial.

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. FINDINGS: 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. INTERPRETATION: 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.

The 10-metre gait speed as a functional biomarker in amyotrophic lateral sclerosis.

There remains a critical need to develop biomarkers of disease progression in amyotrophic lateral sclerosis (ALS). Mobility is a key determinant of disease status and quality of life. The present study assessed the utility of 10-metre gait speed as a functional biomarker of disability in ALS. The gait speed, ALSFRS-R score, body mass index (BMI) and forced vital capacity (FVC), measured in 50 consecutive ALS patients at the time of diagnosis were assessed. ALS patients were managed in the multidisciplinary clinic for up to three years. 10-metre gait speed was significantly reduced in ALS patients with lower limb-onset disease (0.9 ± 0.1 m/s) compared to those with upper limb (1.3 ± 0.1 m/s, p <0.01) and bulbar onset (1.2 ± 0.1 m/s, p <0.01) disease. The 10-metre gait speed correlated with the total ALSFRS-R score (R = 0.6) and the gross motor subscore (R = 0.8, p <0.001). As such, the 10-metre gait speed may serve as a robust marker of disability and disease progression in ALS.

INSPIRATIonAL--INSPIRAtory muscle training in amyotrophic lateral sclerosis.

Respiratory impairment, due to respiratory muscle weakness, is a major cause of morbidity and mortality in patients with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). Threshold loading may strengthen the inspiratory muscles and thereby improve patient prognosis. A phase II, double-blind, randomized-controlled trial was undertaken to determine whether a 12-week inspiratory muscle training programme attenuated the decline in respiratory function and inspiratory muscle strength in patients with ALS/MND. Nine patients were randomized to inspiratory muscle training and 10 to sham training. Primary endpoints were respiratory function (forced vital capacity, vital capacity), lung volumes and inspiratory muscle strength. Patients were assessed before, during and immediately after a 12-week training period, and at eight weeks follow-up. While improvements in inspiratory muscle strength were observed in both treatment arms, there was a non-significant increase in maximum inspiratory pressure of 6.1% in the experimental group compared to controls (standard error of mean, 6.93%; 95% confidence interval -8.58 -20.79; p=0.39). The gains in inspiratory muscle strength were partially reversed during a period of training cessation. In conclusion, inspiratory muscle training may potentially strengthen the inspiratory muscles and slow the decline in respiratory function in patients with ALS/MND.

Riluzole therapy for motor neurone disease: an early Australian experience (1996-2002).

Riluzole is the only therapy proven in clinical trials to prolong survival in patients with motor neurone disease (MND). Prior to its listing by the Australian Pharmaceutical Benefits Advisory Scheme in June 2003, the aim of the present study was to provide Australian patients with MND early access to riluzole and to expand the safety profile data of this therapy. Patients with MND were referred to the programme by neurologists covering the Sydney metropolitan region. To be eligible to receive riluzole, patients had to be aged between 18 and 75 years and have probable or definite MND based on El Escorial criteria, with a disease duration of less than 5 years and a vital capacity greater than 60% before study entry. Patients were prescribed riluzole 50 mg twice daily. Safety data were collected through documentation of adverse events by clinical history in combination with regular laboratory screening. Full blood count, haematocrit, differential white cell counts and serum liver transaminase levels were obtained monthly for 3 months, and then at each 3-monthly visit for 1 year. In total, 25 patients with MND (17 male, 8 female; age range 40-74 years; mean age 59 years) were commenced on riluzole. Of these, 28% had definite MND and the remaining 72% were diagnosed as probable MND, with the majority (84%) having limb-onset MND. At 12 months, 68% of patients continued on riluzole, 16% had died from their disease and 16% ceased riluzole because of side-effects or other reasons, largely disenchantment owing to a perceived lack of efficacy. Haematological and biochemical assays showed no significant alteration during the initial 12-month period. Long-term survival data for patients in the present series suggest a greater benefit for patients who commenced riluzole early in the course of their illness. In conclusion, riluzole was generally tolerated well by Australian patients with MND. Of the few patients who experienced side-effects attributed to riluzole, all were reversible. Issues related to patient perceptions of efficacy highlight the need for patients and treating physicians to maintain realistic expectations of riluzole therapy.