A retrospective analysis of a dose-ranging trial found that those who were administered 100-mg daily riluzole, in comparison with placebo, spend a longer period of time in stage 4 of ALS.
Ammar Al-Chalabi, MBChB, PhD
While it has been known that riluzole can prolong survival for patients with amyotrophic lateral sclerosis (ALS), new research has defined the exact stage in which the medication has this impact—the final clinical stage.1
A research group from the United Kingdom’s King’s College London, including study authors Ammar Al-Chalabi, MBChB, PhD, and Ton Fang, BSc, clarified this prolonging, which adds to the current understanding about the range of survival for ALS—currently understood to be as long as 20 years. Typically, medial survival from symptom onset is about 27.5 months for spinal bulbar onset or 35.9 months for those with spinal onset.
By clarifying the disease into stages, studying the disease can be more functional, according to Fang and the other study authors. They used King’s College’s clinical staging system in this analysis, which was derived from standard clinical observations. Stage 4 of ALS is the stage at which respiratory or nutritional intervention is determined to be clinically necessary, Fang explained to Rare Disease Report, a sister publication of NeurologyLive. On King’s scale of clinical stages, 1 is early disease, 4 is late disease, and 5 is death.
Previously, 100-mg riluzole was found to be associated with multiple benefits in ALS. A 1996 dose-ranging study by Lacomblez et. al. found the therapy to be associated with a 38.6% reduction in mortality,2 and a 1994 trial of the therapy by Bensimon et. al. revealed improvement in survival with riluzole at that dose.3 However, the researchers sought to locate the specific time of this effect: early, late, or over the entire course of the disease’s progression.
Al-Chalabi and colleagues conducted a retrospective analysis of 959 trial participants from the original Lacomblez et al dose-ranging study. All the patients had probable or definite ALS, defined by the El Escorial criteria within a time frame of December 1992 to November 1993, and spread throughout Europe and North America.
In the trial, 237 patients were assigned to 50-mg daily riluzole, 236 patients were administered 100-mg daily riluzole, 244 patients were given 200-mg daily riluzole, and 242 patients were assigned to placebo.
Clinical stages were similar between groups at enrollment, those who were administered 100-mg daily riluzole, in comparison with placebo, spend a longer period of time in stage 4 (hazard ratio [HR], 0.55; 95% CI, 0.36 to 0.83; P = .037). When combining treatment groups and stratifying them by the patient’s stage at enrollment revealed a similar result (HR, 0.638; 95% CI 0.464 to 0.878; P = .006). They also noted that time from stage 2 (P = .83) or stage 3 (P = .88) and the next stage (or death) was no different between the riluzole treatment groups and the placebo group.
When analyzing the results with multistate outcome analysis of treatments (MOAT), the mean number of days spent in stage 4 was statistically higher for those given the treatment drug at the higher doses in comparison with placebo.
Due to the trial’s design, Fang said there was no information available on the participants at stage 1. “Firstly, [these findings are essential in] ensuring that patients and their relatives have the best possible information when making crucial medical decisions, where our research can better inform them of the clinical effects of riluzole,” he said.
The treatment effects at stage 1 still need to be analyzed. Al-Chalabi, Fang, and colleagues stressed that understanding what specifically is being affected by riluzole is of great importance. “A direct clinical implication of our findings is that patients can be told that riluzole extends the later stages of ALS, but it is important to note that it might also extend stage 1, since we have no information on this stage from the trial data,” they wrote.
Prolonging survival in stage 4 compared with earlier stages also has an economic impact, because later stages of ALS are linked with higher costs than the earlier stages. Thus, the study authors wrote, prolonging stage 4 is more expensive than prolonging stages 1 or 2.
“Additionally, our finding that riluzole works at the end stage of ALS leads to a greater understanding of both drug and disease mechanisms, both of which is currently unclear,” Fang said. “Our research also improves the awareness for using staging to determine the effects of treatment in neurodegenerative diseases, where TNM staging is already widely used in cancer research.”
Once it can be understood if riluzole can play a role in prolonging stage 1, clinical trials of treatments in ALS patients and other neurodegenerative diseases can move forward, the study authors concluded.
1. Fang T, Al Khleifat A, Meurgey JH, et al. Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study. Lancet Neurol. 2018; 17(5):416-422.
2. Lacomblez L, Bensimon G, Leigh PN, et al. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet. 1996;347(9013):1425-1431.
3. Bensimon G, Lacomblez L, Meininger V. A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis. N Engl J Med. 1994; 330:585-591.