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ALS/Riluzole Study

A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis

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Year of Publication: 1994

Authors: G. Bensimon, L. Lacomblez, V. Meininger, and the ALS/Riluzole Study Group

Journal: New England Journal of Medicine

Citation: N Engl J Med 1994;330:585-591

Link: https://doi.org/10.1056/NEJM199403033300901

Clinical Question

Does the antiglutamate agent riluzole improve survival and slow functional deterioration in patients with amyotrophic lateral sclerosis?

Bottom Line

Riluzole 100mg/day significantly improved survival in ALS patients, particularly those with bulbar-onset disease, and slowed the rate of muscle strength deterioration. This was the first drug to demonstrate a survival benefit in ALS.

Major Points

  • First controlled trial to demonstrate a survival benefit in ALS
  • 12-month survival was 74% with riluzole vs 58% with placebo (p=0.014), representing a 38.6% reduction in mortality
  • Survival benefit was greatest in bulbar-onset patients: 73% vs 35% at 12 months (p=0.014)
  • Median survival extended by 83 days (532 days riluzole vs 449 days placebo)
  • Rate of muscle strength deterioration reduced by 33.4% with riluzole (p=0.028)
  • Survival advantage persisted at end of placebo-controlled period (49% vs 37%, p=0.046)
  • Adverse effects included asthenia, spasticity, and elevated aminotransferases
  • Treatment effect appeared time-related, with stronger effect in first 12 months
  • Riluzole modulates glutamatergic transmission, supporting glutamate excitotoxicity hypothesis in ALS pathogenesis

Design

Study Type: Prospective, randomized, double-blind, placebo-controlled, stratified trial

Randomization: 1

Blinding: Double-blind. Riluzole and placebo tablets were identical in appearance. Treatment assignments made separately in each center based on randomization codes established by blocking.

Enrollment Period: June 1990 to November 1990

Follow-up Duration: Median 573 days (range 483-632 days); primary analysis at 12 months

Centers: 7

Countries: France, Belgium

Sample Size: 155

Analysis: Intention-to-treat. Survival curves compared by Mantel-Cox (log-rank) statistic, stratified by site of onset. Cox proportional-hazards analysis for prognostic factors. Slopes of clinical scores estimated with unweighted least-squares method. Two-way ANOVA for continuous variables. Statistical power: 90% to detect improvement from 55% to 85% in one-year survival at alpha=5%.

Inclusion Criteria

  • Outpatients aged 20-75 years
  • Clinical status consistent with probable or definite ALS
  • Symptom duration ≤5 years from onset of first symptoms

Exclusion Criteria

  • Signs of conduction blocks of motor or sensory nerves on electromyography
  • Paraproteinemia on immunoelectrophoresis
  • Substantial lesions accounting for clinical signs on CT or MRI
  • Signs of dementia
  • More than 5 years since onset of first symptoms
  • Other incapacitating or life-threatening diseases
  • Forced vital capacity ≤60% of expected value
  • Prior tracheostomy
  • Hepatic or renal dysfunction
  • Pregnancy

Arms

FieldRiluzoleControl
InterventionRiluzole 100mg per day, given as 50mg tablets taken orally twice daily (morning and evening) before mealsIdentical-appearing placebo tablets taken orally twice daily (morning and evening) before meals
DurationUntil death, tracheostomy, or end of placebo-controlled period (median 573 days)Until death, tracheostomy, or end of placebo-controlled period (median 573 days); switched to riluzole after 12-month efficacy analysis

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Survival (death from any cause or tracheostomy) at 12 months and end of placebo-controlled periodPrimary12-month: 45/78 alive (58%); End of study: 29/78 alive (37%); Median survival 449 days12-month: 57/77 alive (74%); End of study: 38/77 alive (49%); Median survival 532 days16.33%0.014 (12 months); 0.046 (end of study)
Survival at 12 months - Bulbar-onset subgroupSecondary6/17 alive (35%); Median survival 239 days11/15 alive (73%); Median survival not reached after 476 days0.014
Survival at end of study - Bulbar-onset subgroupSecondary3/17 alive (18%)8/15 alive (53%)0.013
Survival at 12 months - Limb-onset subgroupSecondary39/61 alive (64%); Median survival 523 days46/62 alive (74%); Median survival 531 days0.17
Survival at end of study - Limb-onset subgroupSecondary26/61 alive (43%)30/62 alive (48%)0.355
Rate of muscle-testing score deterioration (33.4% reduction)SecondaryFaster deteriorationSlower deterioration0.028
Rate of limb functional score deteriorationSecondaryFaster deteriorationSlower deterioration (trend)Not significant
Rate of bulbar functional score deteriorationSecondaryFaster deteriorationSlower deterioration (trend)Not significant
Asthenia (worsening)AdverseNot specifiedMore frequent
Spasticity (worsening)AdverseNot specifiedMore frequent
Elevated ALT (>3x ULN)Adverse3 patients6 patients
Elevated ASTAdverse3 patients11 patients
Elevated ALT and AST combinedAdverse0 patients5 patients
Mild-to-moderate hypertensionAdverseNot specifiedReported
Withdrawal from treatmentAdverse17 patients (9 due to adverse experiences)27 patients (19 due to adverse experiences)

Subgroup Analysis

Randomization was stratified by site of disease onset (bulbar vs limb). The treatment effect was significantly greater in bulbar-onset patients (38% absolute survival difference at 12 months) compared to limb-onset patients (10% absolute difference, not statistically significant). The authors caution that such striking subgroup differences must be interpreted carefully as they can arise by chance. Cox proportional-hazards analysis identified age, duration of disease, FVC, bulbar-function score, tiredness score, and stiffness score as significant prognostic variables; treatment effect remained significant after adjustment for these factors at 12 months (p=0.005) but only trended toward significance at study end (p=0.058).

Criticisms

  • Relatively small sample size (155 patients) limits statistical power, especially for subgroup analyses
  • Higher withdrawal rate in riluzole group (27 vs 17) may have led to underestimation of treatment benefit in ITT analysis
  • 24 patients did not meet all entry criteria but were retained in analysis under blinded conditions
  • Striking difference between bulbar and limb-onset subgroups must be interpreted cautiously as may arise by chance
  • Treatment effect appeared to diminish over time (stronger at 12 months than 21 months)
  • Mechanism of action not fully understood
  • Limited functional outcome data - only muscle-testing score reached significance
  • Single dose studied (100mg/day) - dose-response not established
  • Short recruitment period (5 months) at limited number of centers
  • Patients switched to riluzole after 12-month analysis, limiting long-term placebo comparison
  • Aminotransferase elevations more frequent with riluzole, requiring monitoring
  • Quality of life impact not formally assessed

Funding

Supported by Rhone-Poulenc Rorer

Based on: ALS/Riluzole Study (New England Journal of Medicine, 1994)

Authors: G. Bensimon, L. Lacomblez, V. Meininger, and the ALS/Riluzole Study Group

Citation: N Engl J Med 1994;330:585-591

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