OBJECTIVE:

In patients with amyotrophic lateral sclerosis, long term treatment with riluzole has been reported to improve survival or tracheostomy-free survival in comparison with placebo. We conducted a pharmacoeconomic analysis for estimating the cost per life-year gained using this drug.

DESIGN:

This study was an incremental cost-effectiveness lifetime analysis.

SETTING:

The clinical material was derived from 2 placebo-controlled randomised controlled trials comparing riluzole versus usual care without riluzole, which were identified through a literature search based on the IOWA and the Medline systems.

PATIENTS AND INTERVENTIONS:

The study included 633 patients with amyotrophic lateral sclerosis. Patient-level information was retrieved from 313 patients treated with riluzole and 320 patients assigned to placebo. Survival after randomisation was compared between the 2 groups using standard statistics (log-rank test and Cox analysis), whereas the lifetime survival gain was estimated using Gompertz extrapolation. Cost data relative to the expenditure for healthcare resources were obtained from published information (using the US average wholesale price for the acquisition cost of riluzole). Sensitivity testing assessed the impact of different cost-of-illness assumptions for treated and untreated patients.

MAIN OUTCOME MEASURES AND RESULTS:

Our primary analysis showed that treatment with riluzole significantly prolonged survival [death risk = 0.77; 95% confidence interval (CI): 0.62 to 0.96; p = 0.022]. The lifetime survival gain (including 3% annual discounting) was, on average, 2.3 months per patient, while the incremental cost was around $US12,000 per patient. Hence, the cost-effectiveness ratio of riluzole versus usual care without riluzole was $US62,609 per life-year gained (discounted dollars per discounted years; 95% CI.: $US13,458 to $US205,714). The sensitivity analysis, considering different values of national cost for riluzole, suggested an interval for this parameter ranging from $US45,048 to $US62,609.

CONCLUSIONS:

Our study indicates that in patients with amyotrophic lateral sclerosis, riluzole has an unfavourable cost-effectiveness ratio or, at best, a borderline pharmacoeconomic profile.

Treatment with the neuroprotective drug riluzole has previously been shown to increase the probability of survival in patients with amyotrophic lateral sclerosis. This report describes a placebo-controlled, double-blind randomised clinical trial of riluzole carried out in ALS patients with advanced stage disease or aged over 75 years. The primary objective was to enable access to treatment to patients excluded from the pivotal trial which was run in parallel. Another goal was to assess the safety of riluzole in patients with advanced-stage disease. One hundred and sixty-eight patients were included, randomised to either riluzole 50 mg b. i. d. or to placebo, and treated for eighteen months. Riluzole was well-tolerated in this patient population, and the adverse events observed were similar in nature and frequency to those observed in previously published clinical trials in patients included in pivotal trials. The study could not include enough patients to reach adequate power to detect differences in survival between the two treatment groups, and no such difference was in fact observed. In conclusion, riluzole is well-tolerated in ALS patients with advanced stage disease.

CRD COMMENTARY:

This was a well-conducted and reported review. A thorough search of the literature was undertaken. Trials were included on the basis of criteria that were appropriate to the review question. The validity of the individual trials was assessed and presented with other relevant study details. These trials were summarised in a sensible manner, with a discussion of the clinical and statistical heterogeneity between the studies.
The authors' conclusions follow from the evidence presented.

BACKGROUND:

It has been hypothesized that glutamatergic transmission may be altered in Tourette syndrome. In this study, we explored the efficacy of a glutamate agonist (D-serine) and antagonist (riluzole) as tic-suppressing agents in children with Tourette syndrome.

METHODS:

We performed a parallel three-arm, 8-week, double-blind, randomized placebo-controlled treatment study in children with Tourette syndrome. Each child received 6 weeks of treatment with D-serine (maximum dose 30 mg/kg/day), riluzole (maximum dose 200 mg/day), or placebo, followed by a 2-week taper. The primary outcome measure was effective tic suppression as determined by the differences in the Yale Global Tic Severity Scale score; specifically, the total tic score and the combined score (total tic score + global impairment) between treatment arms after 6 weeks of treatment. Mann-Whitney U tests were performed to analyze differences between each group and the placebo group.

RESULTS:

Twenty-four patients (males = 21, ages 9-18) enrolled in the study; one patient dropped out before completion. Combined Yale Global Tic Severity Scale score and total tic scores improved in all groups. The 6-week mean percent improvement of the riluzole (n = 10), D-serine (n = 9), and placebo (n = 5) groups in the combined Yale Global Tic Severity Scale score were 43.7, 39.5, and 30.2 and for total tic scores were 38.0, 25.0, and 34.0, respectively. There were no significant differences in Yale Global Tic Severity Scale score or total tic score, respectively, between the riluzole and placebo (P = 0.35, 0.85) or D-serine and placebo (P = 0.50, 0.69) groups.

CONCLUSION:

Tics diminished by comparable percentages in the riluzole, D-serine, and placebo groups. These preliminary data suggest that D-serine and riluzole are not effective in tic suppression.

The N-methyl-d-aspartate (NMDA) glutamate receptor antagonist ketamine may have rapid, albeit transient, antidepressant properties. This study in patients with treatment-resistant major depression (TRD) aimed to (1) replicate the acute efficacy of single-dose intravenous (i.v.) ketamine; (2) test the efficacy of the glutamate-modulating agent riluzole in preventing post-ketamine relapse; and (3) examine whether pretreatment with lamotrigine would attenuate ketamine's psychotomimetic effects and enhance its antidepressant activity. Twenty-six medication-free patients received open-label i.v. ketamine (0.5 mg/kg over 40 min). Two hours prior to infusion, patients were randomized to lamotrigine (300 mg) or placebo. Seventeen patients (65%) met response criterion (≥50% reduction from baseline on the Montgomery-Asberg Depression Rating Scale) 24 h following ketamine. Lamotrigine failed to attenuate the mild, transient side-effects associated with ketamine and did not enhance its antidepressant effects. Fourteen patients (54%) met response criterion 72 h following ketamine and proceeded to participate in a 32-d, randomized, double-blind, placebo-controlled, flexible-dose continuation trial of riluzole (100-200 mg/d). The main outcome measure was time-to-relapse. An interim analysis found no significant differences in time-to-relapse between riluzole and placebo groups [log-rank 2=0.17, d.f.=1, p=0.68], with 80% of patients relapsing on riluzole vs. 50% on placebo. The trial was thus stopped for futility. This pilot study showed that a sub-anaesthetic dose of i.v. ketamine is well-tolerated in TRD, and may have rapid and sustained antidepressant properties. Riluzole did not prevent relapse in the first month following ketamine. Further investigation of relapse prevention strategies post-ketamine is necessary. Copyright © 2009 CINP.

Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000 mg per day) may be efficacious in slowing down disease progression when added to riluzole.

METHODS:

160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000 mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEP's were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an "intent-to-treat" (ITT) population which included all randomised patients who had received at least one treatment dose (n = 160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion.

RESULTS:

Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance.

CONCLUSION:

Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.

The N-methyl-D-aspartate antagonist ketamine has rapid antidepressant effects in patients with treatment-resistant major depression (TRD); these effects have been reported to last for 1 week in some patients. However, the extent and duration of this antidepressant effect over longer periods has not been well characterized under controlled conditions. Riluzole, a glutamatergic modulator with antidepressant and synaptic plasticity-enhancing effects, could conceivably be used to promote the antidepressant effects of ketamine. This study sought to determine the extent and time course of antidepressant improvement to a single-ketamine infusion over 4 weeks, comparing the addition of riluzole vs placebo after the infusion. Forty-two subjects (18-65) with TRD and a Montgomery-Asberg Depression Rating Scale (MADRS) score of ≥ 22 received a single intravenous infusion of ketamine (0.5 mg/kg). Four to six hours post-infusion, subjects were randomized to double-blind treatment with either riluzole (100-200 mg/day; n=21) or placebo (n=21) for 4 weeks. Depressive symptoms were rated daily. A significant improvement (P<0.001) in MADRS scores from baseline was found. The effect size of improvement with ketamine was initially large and remained moderate throughout the 28-day trial. Overall, 27% of ketamine responders had not relapsed by 4 weeks following a single ketamine infusion. The average time to relapse was 13.2 days (SE=2.2). However, the difference between the riluzole and placebo treatment groups was not significant, suggesting that the combination of riluzole with ketamine treatment did not significantly alter the course of antidepressant response to ketamine alone.

BACKGROUND:

The glutamate system seems to be an important contributor to the pathophysiology of mood and anxiety disorders. Thus, glutamatergic modulators are reasonable candidate drugs to test in patients with mood and anxiety disorders. Riluzole, a neuroprotective agent with anticonvulsant properties approved for the treatment of amyotrophic lateral sclerosis (ALS) is one such agent.

OBJECTIVE:

To assess the potential risks and benefits of riluzole treatment in psychiatric patients.

METHODS:

A PubMed search was performed using the keywords 'riluzole', 'inhibitor of glutamate release' and 'glutamatergic modulator' to identify all clinical studies and case reports involving riluzole in psychiatric patients.

RESULTS/CONCLUSION:

Riluzole's side effect profile is favorable and preliminary results regarding riluzole for the treatment of severe mood, anxiety and impulsive disorders are encouraging.

INTRODUCTION:

Increasing evidence suggests that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of paralysis in transgenic mice expressing a mutation in superoxide dismutase found in certain forms of familial ALS. The current study was designed to determine whether alpha-tocopherol (500 mg b.i.d.) may be efficacious in the treatment of ALS.

METHODS:

Two hundred and eighty-nine patients with ALS of less than 5 years duration, treated with riluzole, were enrolled in this study, and were randomly assigned to receive either alpha-tocopherol or placebo daily for one year. The primary outcome measure was the rate of deterioration of function assessed by the modified Norris limb scale. Patients were assessed at entry, and every 3 months thereafter during the study period. Survival was also recorded. Biochemical markers of oxidative stress were measured in a subset of patients on entry and after 3 months of treatment.

RESULTS:

After 12 months of treatment, alpha-tocopherol had no effect on the primary outcome measure. Survival was not influenced by treatment. Among secondary outcome measures, patients given alpha-tocopherol were less likely to progress from the milder state A to the more severe state B (P=0.046) of the ALS Health State scale. After 3 months treatment, analysis of oxidative stress markers showed an increase in glutathione peroxidase activity in plasma (P = 0.0389) and a decrease in plasma levels of thiobarbituric acid reactive species (P = 0.0055) in the group of patients given alpha-tocopherol in combination with riluzole.

CONCLUSION:

Although alpha-tocopherol did not appear to affect the survival and motor function in ALS, patients receiving riluzole plus alpha-tocopherol remained longer in the milder states of the ALS Health State scale and showed, after 3 months, changes in biochemical markers of oxidative stress. Further studies are required to confirm the greater sensitivity of the ALS Health State scale over other clinical endpoints.

Primary objective:

* The primary objective of the study is to establish that riluzole slows down (1) the decrease in total functional capacity (TFC), (2) the increase of the motor score of the Unified Huntington\'s Disease Rating Scale (UHDRS) as well as (3) the increase of a combined score of these.

Secondary objectives:

Secondary objectives are to assess

* changes in the other UHDRS subscales
* the number of patients who need antichoreic treatment and the time until this treatment has to be initiated
* the safety/tolerability of riluzole in Huntington patients