Riluzole increased tracheostomy-free survival and was well tolerated in ALS
ACP J Club. 1996 Nov-Dec;125:68. doi:10.7326/ACPJC-1996-125-3-068
Lacomblez L, Bensimon G, Leigh PN, Guillet P, Meininger V, for the Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet. 1996 May 25;347:1425-31. [PubMed ID: 8676624]
To determine whether riluzole increases tracheostomy-free survival in adults with amyotrophic lateral sclerosis (ALS) and to determine its efficacy at different doses.
Randomized, double-blind, placebo-controlled trial with median 18-month follow-up.
30 clinical centers in North America and Europe.
959 patients (mean age 57 y, 60% men) who had clinically definite ALS (295 patients with bulbar-onset and 664 with limb-onset ALS) ≤ 5 years in duration. Inclusion criteria were forced vital capacity of ≥ 60% of the expected value and activities of aspartate and alanine aminotransferase of no more than twice the normal upper limit. Exclusion criteria were tracheostomy, renal dysfunction, other serious illness, or pregnancy.
242 patients were allocated to placebo; 237 to riluzole, 50 mg/d; 236 to riluzole, 100 mg/d; and 244 to riluzole, 200 mg/d. After 18 months of treatment, patients could choose to take 100 mg/d.
Main outcome measures
Tracheostomy-free survival defined as death, tracheostomy, or intubation leading to tracheostomy and adverse events.
Analysis was by intention to treat. 528 patients (55%) were alive without a tracheostomy at the end of the study: 50.4% in the placebo group, 55.3% in the 50-mg riluzole group, 56.8% in the 100-mg riluzole group, and 57.8% in the 200-mg riluzole group. The groups did not differ for rates of tracheostomy (3.9% overall). The relative risk (RR) for tracheostomy-free survival at 18 months was adjusted for prognostic factors (age, disease duration, bulbar signs at entry, weight, vital capacity, stiffness, tiredness, muscle strength, clinical general impression, and country of treatment). Patients who were allocated to 50 mg of riluzole compared with patients who were allocated to placebo had an adjusted RR of 0.76, 95% CI 0.59 to 0.99, P = 0.04). Similar results were shown in the comparison of 100 mg of riluzole with placebo (RR 0.65, CI 0.50 to 0.85, P = 0.002) and 200 mg of riluzole with placebo (RR 0.61, CI 0.47 to 0.80, P < 0.001). The treatment effects did not differ for sites of disease onset (P = 0.62). The groups also did not differ for the number of patients with adverse effects and with treatment withdrawal (11%, 10%, 14%, and 15% for the placebo, 50-mg, 100-mg, and 200-mg groups, respectively).
Riluzole increased tracheostomy-free survival and was well tolerated in patients with amyotrophic lateral sclerosis.
Source of funding: Rhône Poulenc-Rorer (riluzole and placebo).
For article reprint: Professor V. Meininger, Service de Neurologie, Division Mazarin, Hôpital de la Salpêtrière, 47 boulevard de L'Hôpital, 75651 Paris Cedex 13, France. FAX 4424-3269.
ALS is characterized by fatal and inexorably progressive weakness. A treatment to improve this dismal situation is desperately needed. This large, well-designed multicenter, multinational, randomized controlled trial of riluzole, a glutamate-release inhibitor, partially meets this need.
Although the differences in tracheostomy-free survival at 18 months relative to placebo are statistically significant, their clinical significance is small. With the adjustment for 11 other variables in a proportional hazards model, the apparent drug effect is stronger so that at 18 months, the 50-, 100-, and 200-mg doses of riluzole decreased the RR for death or tracheostomy by 24%, 35%, and 39%, respectively.
None of the 3 functional scores (muscle strength testing, limb scores, or bulbar scores), however, showed a treatment effect, nor did the other secondary outcome variables (respiratory function test, visual analog scales, or clinician's general impression of severity). Quality of life was not formally measured.
Clinical or laboratory adverse events that caused treatment withdrawals were typically mild and reversible, and no serious adverse events were noted. Drug-related treatment withdrawal was more common in the higher-dose groups, whereas lack of efficacy or withdrawal of consent were more common reasons for withdrawal in the placebo and low-dose groups. In a preliminary study (1), a small treatment effect was also observed but only in patients with disease of bulbar onset. This difference did not persist in this study.
In summary, riluzole is safe but, at best, has limited effectiveness.
Paul O'Connor, MD, MSc
St. Michael's HospitalToronto, Ontario, Canada