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Riluzole Dose-Ranging Study

Dose-Ranging Study of Riluzole in Amyotrophic Lateral Sclerosis

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Year of Publication: 1996

Authors: Lacomblez L, Bensimon G, Leigh PN, ..., and the ALS/Riluzole Study Group II

Journal: Lancet

Citation: Lacomblez L et al. Lancet. 1996;347(9013):1425-1431

Link: https://pubmed.ncbi.nlm.nih.gov/8676624/

Clinical Question

Does riluzole improve survival in ALS patients in a dose-dependent manner, and what is the optimal dose?

Bottom Line

Riluzole significantly improved tracheostomy-free survival with a dose-response relationship. The 100 mg/day dose offered the best benefit-to-risk ratio (adjusted HR 0.65, p=0.002), establishing it as the standard dose worldwide.

        Major Points
        Confirmed survival benefit of riluzole in larger population (n=959)
Significant dose-response relationship for mortality risk
100 mg/day: adjusted HR 0.65 (p=0.002) -- best benefit-to-risk ratio
200 mg/day slightly greater efficacy (HR 0.61) but more adverse events
Established 100 mg/day as standard riluzole dose worldwide

      

Design

Study Type: Double-blind, placebo-controlled, dose-ranging, multicenter RCT

Randomization: 1

Blinding: Double-blind

Enrollment Period: 1992-1994

Follow-up Duration: Median 18 months

Centers: 30

Countries: France, United Kingdom, Belgium, Spain, Germany

Sample Size: 959

Analysis: Intention-to-treat; Cox proportional hazards model adjusted for prognostic factors

Inclusion Criteria

Familial or sporadic ALS diagnosis (clinically probable or definite)
Disease duration less than 5 years
Forced vital capacity (FVC) greater than 60% of predicted
Age 18 to 75 years

Exclusion Criteria

Tracheostomy
Requirement for assisted ventilation
FVC 60% or less of predicted
Significant concurrent medical conditions

Arms

Field	Control	Riluzole 50 mg/day	Riluzole 100 mg/day	Riluzole 200 mg/day
Intervention	Matching placebo	Riluzole 50 mg/day	Riluzole 100 mg/day (50 mg BID)	Riluzole 200 mg/day
Duration	18 months	18 months	18 months	18 months

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Tracheostomy-free survival at 18 months	Primary	50.4% alive without tracheostomy	100 mg/day: 56.8% alive without tracheostomy	0.65	Adjusted p=0.002
Tracheostomy-free survival - 50 mg/day	Secondary	50.4%	55.3%	0.76	p=0.04
Tracheostomy-free survival - 200 mg/day	Secondary	50.4%	57.8%	0.61	p=0.0004
Asthenia	Adverse	12%	19% (pooled riluzole)
Nausea	Adverse	11%	16% (pooled riluzole)
Decreased lung function	Adverse	9%	10% (pooled riluzole)
Abdominal pain	Adverse	4%	5% (pooled riluzole)
Hypertension	Adverse	4%	5% (pooled riluzole)
Vomiting	Adverse	2%	4% (pooled riluzole)
Dizziness	Adverse	3%	4% (pooled riluzole)
Dry mouth	Adverse	3%	4% (pooled riluzole)
Insomnia	Adverse	3%	4% (pooled riluzole)
Circumoral paresthesia	Adverse	0%	2% (pooled riluzole)
Somnolence	Adverse	1%	2% (pooled riluzole)
Hepatic enzyme elevations (ALT >ULN)	Adverse		~50% above ULN; ~8% above 3x ULN; 2% above 5x ULN; maximum elevations within first 3 months

Subgroup Analysis

Riluzole benefit consistent across bulbar vs limb onset subgroups. Dose-response relationship significant across all three dose levels.

Criticisms

Unadjusted comparison for 100 mg did not reach significance (p=0.076); required covariate adjustment for significance
No functional outcome measure (muscle strength, pulmonary function) showed significant treatment effect -- survival benefit without functional improvement
Survival benefit modest: ~6% absolute difference at 18 months for 100 mg dose, corresponding to approximately 60 days median survival extension
Dose-related hepatotoxicity: ~50% had ALT elevation above ULN, ~8% above 3x ULN
Industry-funded (Rhone-Poulenc Rorer) with potential conflict of interest
200 mg dose slightly more effective (HR 0.61) but substantially more toxic, raising questions about optimal dosing
Study predated modern ALS functional scales like ALSFRS-R; limited functional outcome assessment

Funding

Rhone-Poulenc Rorer

Based on: Riluzole Dose-Ranging Study (Lancet, 1996)

Authors: Lacomblez L, Bensimon G, Leigh PN, ..., and the ALS/Riluzole Study Group II

Citation: Lacomblez L et al. Lancet. 1996;347(9013):1425-1431

Content summarized and formatted by NeuroTrials.ai.

Riluzole Dose-Ranging Study

(1996)

Objective

To confirm that riluzole decreases mortality in ALS and to determine the optimal dose by comparing 50 mg, 100 mg, and 200 mg daily doses against placebo

Study Summary

• All riluzole doses showed a survival benefit with a significant dose-response relationship; the 100 mg dose had the best benefit-to-risk ratio (adjusted HR 0.65, p=0.002; ~60 days median survival extension)
• Dose-related hepatotoxicity: ~50% had ALT above ULN, ~8% above 3x ULN; asthenia (19% vs 12%) and nausea (16% vs 11%) most common AEs; no functional outcome measure showed significant treatment effect despite survival benefit

Intervention

Oral riluzole at 50 mg, 100 mg, or 200 mg daily vs placebo

Inclusion Criteria

Clinically probable or definite ALS, disease duration less than 5 years, FVC >60%, age 18-75

Study Design

Arms: Riluzole 50 mg/day vs Riluzole 100 mg/day vs Riluzole 200 mg/day vs Placebo

Patients per Arm: Placebo: 241, Riluzole 50 mg: 236, Riluzole 100 mg: 235, Riluzole 200 mg: 244

Outcome

• 18-month tracheostomy-free survival: Placebo 50.4%, 50 mg 55.3% (HR 0.76, p=0.04), 100 mg 56.8% (HR 0.65, p=0.002), 200 mg 57.8% (HR 0.61, p=0.0004)
• 100 mg/day best benefit-to-risk ratio (~60 days median survival extension); established as standard dose worldwide
• Hepatotoxicity: ~50% ALT>ULN, ~8%>3x ULN; no functional outcome measure significant; AEs: asthenia 19% vs 12%, nausea 16% vs 11%

Bottom Line

Major Points

Confirmed survival benefit of riluzole in larger population (n=959)
Significant dose-response relationship for mortality risk
100 mg/day: adjusted HR 0.65 (p=0.002) -- best benefit-to-risk ratio
200 mg/day slightly greater efficacy (HR 0.61) but more adverse events
Established 100 mg/day as standard riluzole dose worldwide

Study Design

Study Type: Double-blind, placebo-controlled, dose-ranging, multicenter RCT
Randomization: Yes
Blinding: Double-blind
Sample Size: 959
Follow-up: Median 18 months
Centers: 30
Countries: France, United Kingdom, Belgium, Spain, Germany

Primary Outcome

Definition: Tracheostomy-free survival at 18 months

Control	Intervention	HR/OR	P-value
50.4% alive without tracheostomy	100 mg/day: 56.8% alive without tracheostomy	0.65	Adjusted p=0.002

Limitations & Criticisms

Unadjusted comparison for 100 mg did not reach significance (p=0.076); required covariate adjustment for significance
No functional outcome measure (muscle strength, pulmonary function) showed significant treatment effect -- survival benefit without functional improvement
Survival benefit modest: ~6% absolute difference at 18 months for 100 mg dose, corresponding to approximately 60 days median survival extension
Dose-related hepatotoxicity: ~50% had ALT elevation above ULN, ~8% above 3x ULN
Industry-funded (Rhone-Poulenc Rorer) with potential conflict of interest
200 mg dose slightly more effective (HR 0.61) but substantially more toxic, raising questions about optimal dosing
Study predated modern ALS functional scales like ALSFRS-R; limited functional outcome assessment

Citation

Lacomblez L et al. Lancet. 1996;347(9013):1425-1431

View Original Publication →

Riluzole Dose-Ranging Study

Dose-Ranging Study of Riluzole in Amyotrophic Lateral Sclerosis

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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