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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a median survival of 3 years. Currently, riluzole is the only drug that can prolong the life expectancy of patients with ALS.1 In the original trial, riluzole prolonged median survival by approximately 3 months, although no effect on function was observed.1 Therefore, it is unknown whether the survival benefit of riluzole occurs at an early stage, late stage or is spread throughout the course of the disease.
Interestingly, in a recent reanalysis of the riluzole trial only a late-stage effect of riluzole was found.2 The investigators noted, however, that the earliest stage could not be analysed because of inclusion criteria and that further studies are needed.2
The question, therefore, remains whether riluzole also prolongs the earliest disease stage. This information is vital as, from a patient’s perspective, prolonging the earliest disease stages, when disability is lowest and quality of life is highest, is most desirable. We aim, therefore, to determine the timing of benefit of riluzole in a large cohort of patients with ALS.
We used the Pooled Resource Open-Access ALS Clinical Trial database which contains data from 23 phase II/III clinical trials, including the riluzole trial.1
Two staging algorithms in ALS, Milano-Torino (MITOS) and King’s staging, were used to estimate clinical stage from clinical trial data (ALS Functional Rating Scale-Revised [ALSFRS-R] scores, weight and vital capacity measurements).2 3 There are five MITOS stages, based on autonomy loss in four key domains of the ALSFRS-R: walking/self-care, swallowing, communicating and breathing.3 King’s stages range from 1 (early disease) to stage 4 (late disease) and stages 1, 2 and 3 correspond to symptoms in one, two or three body regions (ie, bulbar, upper and/or lower limbs).3 King’s stage 4 is defined as either nutritional or respiratory failure.2 In both staging systems, stage 5 is defined as death.3
We applied an identical methodology that was used to reanalyse the riluzole trial.2 The log-rank test was used to compare the distribution of stage durations for riluzole users and non-users. Cox regression was used to confirm the effect of riluzole per stage. The event per stage was progressing to a higher stage or death. Patients were censored after 18 months.
There were 4571 patients and 45 411 observations with a mean of 10 observations and 13 months of follow-up. Of all patients, 3308 (72%) used riluzole and 1263 (28%) did not. Baseline characteristics were similar for both groups, except for diagnostic delay which was longer for the no riluzole group (13 vs 10 months). There were 1162 deaths, resulting in an 18-month survival probability of 0.66 (95% CI 0.64 to 0.67). Riluzole use was associated with a 20% lower risk of death during the 18 months of follow-up (HR 0.80, 95% CI 0.71 to 0.91, p<0.001).
The largest effect of riluzole was in King’s stage 4 (HR 0.71, 95% CI 0.61 to 0.82, p<0.001) (figure 1); a smaller, although significant, effect was found in King’s stage 1 (HR 0.86, 95% CI 0.76 to 0.99, p=0.03) and MITOS stage 1 (HR 0.84, 95% CI 0.75 to 0.93, p<0.001). Additionally, riluzole prolonged the median stage duration of King’s stage 1: 4.8 (95% CI 4.1 to 5.8) vs 3.5 (95% CI 3.1 to 4.2) and MITOS stage 1: 8.5 (95% CI 8.1 to 9.0) vs 7.0 (95% CI 6.4 to 8.1) for riluzole users and non-users, respectively. The probability of remaining in King’s stage 4 after 18 months was higher for riluzole users than for non-users: 0.53 (95% CI 0.49 to 0.57) and 0.42 (95% CI 0.37 to 0.48), respectively. In contrast, we found no effect in King’s stages 2 and 3 and MITOS stages 0, 2, 3 and 4.
We determined the timing of benefit of riluzole in a large cohort of patients with ALS and found that riluzole prolongs MITOS stage 1 and King’s stages 1 and 4. These results show early efficacy of riluzole and also confirm the previously observed effect in King’s stage 4.2 Encouraging all patients to consider using riluzole is important, as it is currently unknown to what extent individual patients will benefit from riluzole. Riluzole may work via at least two mechanisms1: an early effect, possibly due to neuroprotection from excitotoxicity, and2 a late effect, possibly on respiratory function.
An early benefit of riluzole is consistent with a study that showed partial normalisation of central and peripheral neurophysiological studies within weeks of initiation of riluzole treatment in patients with early stage ALS.4
We observed no effect of riluzole in MITOS stages 0, 2, 3 and 4 or King’s stages 2 and 3. There may be several explanations. First, riluzole may only prolong MITOS stage 1 and King’s stages 1 and 4. Second, selection in clinical trials might prevent detection of treatment effects, as a selected subset of patients is enrolled. Or, lastly, the use of varying outcome definitions could lead to this result. For example, in stage 4, the event is death, whereas in stage 3, the event is either progressing to stage 4 or death. Combining clinical milestones with survival into a composite outcome may dilute the effect size and decrease statistical power in a clinical trial.5 This dilution can only occur in stages 0 to 3, when a relatively low informative event (progressing to a stage other than death) is combined with the informative event death. This may result in a failure to detect treatment effects and could explain why the effect of riluzole is relatively largest in King’s stage 4. It may, therefore, be worthwhile altering our approach when assessing interactions between staging and treatments in future trials (eg, estimating stage duration as a continuous outcome measure, or increasing the threshold for leaving a stage).
In conclusion, riluzole prolongs MITOS stage 1 and King’s stages 1 and 4 in patients with ALS. Knowledge about the timing of benefit of any treatment is important, as it can be of help when counselling patients. Clinical staging algorithms may aid in the identification of subgroups of patients with ALS who could benefit from current and future treatments.
Contributors AdJ, RPAvE and LHvdB designed the study. AdJ analysed the data and drafted the manuscript. RPAvE and LHvdB critically reviewed the manuscript.
Funding This study was supported by the Netherlands ALS Foundation.
Competing interests AdJ and RPAvE report no disclosures. LHvdB reports grants from Netherlands ALS Foundation, the Netherlands Organization for Health Research and Development (Vici scheme), the Netherlands Organization for Health Research and Development (SOPHIA, STRENGTH, ALS-CarE project), funded through the EU Joint Programme – Neurodegenerative Disease Research, JPND), served on the Scientific Advisory Board of Biogen, Cytokinetics, Prinses Beatrix SpierFonds, and the Latran Foundation.
Patient consent for publication Not required.
Ethics approval The Pooled Resource Open-Access ALS Clinical Trial database is institutional review board approved and only uses anonymised data. Patients consented to participate during the individual trials.
Provenance and peer review Not commissioned; externally peer reviewed.
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