Riluzole: real-world evidence supports significant extension of median survival times in patients with amyotrophic lateral sclerosis

Figures & data

Table 1 Summary of survival outcomes of randomized controlled trials conducted on riluzole in ALS patients

Parameters	Bensimon et al^Citation26	Lacomblez et al^Citation27,Citation59,a	Bensimon et al^Citation29	Yanagisawa et al^Citation28
Treatment/comparator	Riluzole 100 mg/d/placebo	Riluzole 50, 100, and 200 mg/d/placebo	Riluzole 100 mg/d/placebo	Riluzole 100 mg/d/placebo
Design/randomized?/double-blind?/ITT?	RCT/yes/yes/yes	RCT/yes/yes/yes	RCT/yes/yes/yes	RCT/yes/yes/yes
Country/number of centers	France, Belgium/7	France, Belgium, UK, Spain, Germany, USA, Canada/30	France, Belgium/9	Japan/48
End of study	21 months	18 months	18 months	21 months
No. patients: (total) placebo/riluzole	(155) 78/77	(959) 242/717 (riluzole: 237/236/244, respectively)	(168) 86/82	(195) 97/98
Comparison of all ALS cases (data relate to end of study unless otherwise stated)
Median tracheostomy-free survival time (placebo/riluzole)	14.9/17.7 months	13.5/16.5 months	NR	NR
Reduction in mortality with riluzole	12 months: 38.6%; end of study 19.4%	NR
Unadjusted RR [or HR] (95% CI) of tracheostomy-free survival	NR	All doses pooled 0.81 (0.66–0.99) p=0.048; 50 mg/d 0.85 (0.66–1.11) p=0.25; 100 mg/d 0.79 (0.6–1.02) p=0.076; 200 mg/d 0.79 (0.61–1.03) p=0.075 (log-rank)	[1.05 (0.73–1.50) p=0.77]
Adjusted RR (95% CI) of tracheostomy-free survival using Cox proportional hazard method	12 months: 0.43 (0.24–0.77) p=0.005; end of study: 0.66 (0.42–1.02) p=0.058	All doses pooled 0.67 (0.54–0.83) p=0.0003; 50 mg/d 0.76 (0.59–0.99) p=0.04; 100 mg/d 0.65 (0.50–0.85) p=0.002; 200 mg/d 0.61 (0.47–0.80), p=0.0004	NR
Meta-analyses by Stewart et al^Citation33
Comparison of all ALS cases – riluzole 50, 100, and 200 mg/d vs. placebo: unadjusted tracheostomy-free survival
No. placebo/riluzole events	49 of 78/39 of 77	120 of 242/311 of 717	64 of 86/60 of 82	NR
HR (95% CI)	0.64 (0.41–1.00) p=0.050b	0.80 (0.63–1.01) p=0.058b	0.98 (0.66–1.46) p=0.93
Pooled data#1 weight (%)	15.9	59.0	25.1	0.0
HR (95% CI)	0.83 (0.69–0.99)b			NA
Pooled data#2 weight (%)	21.3	78.7	0	0
HR (95% CI)	0.76 (0.62–0.94)b		NA	NA
Comparison of bulbar onset ALS cases – riluzole 100 mg/d vs. placebo: unadjusted tracheostomy-free survival or [progression-free survival]
Placebo/Riluzole events	14 of 17/7 of 15		20 of 28/28 of 29	[19 of 28/20 of 28]
HR (95% CI)	0.29 (0.11–0.75) p=0.010b	NR	1.94 (1.08–3.50) p=0.025	[1.05 (0.53–2.09)] p=0.891
Comparison of limb onset ALS cases – riluzole 100 mg/d vs. placebo: unadjusted tracheostomy-free survival or [progression-free survival]
Placebo/riluzole events	35 of 61/32 of 62	NR	44 of 58/32 of 53	[Early limb 23 of 36/27 of 42] [Advanced limb 24 of 33/24 of 28]
HR (95% CI)	0.80 (0.48–1.33) p=0.394b	NR	0.73 (0.46–1.15) p=0.173	[Early limb 1.07 (0.58–1.97)] p=0.821 [Advanced limb 1.48 (0.76–2.87)] p=0.247

Notes:

Notes:

a Data used for post hoc analysis in 241 placebo and 713 riluzole ALS patients reported significant prolongation of milder health states in patients taking riluzole (p<0.05).⁶⁰

b Favors riluzole treatment.

Abbreviations: ALS, amyotrophic lateral sclerosis; CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; NA, not applicable; NP, not performed; NR, not reported; RCT, randomized controlled trial; RR, relative risk.

Table 2 Summary of survival outcomes based on real-world evidence on riluzole in ALS patients

Parameters	Meininger et al^Citation48	Brooks et al^Citation49	Turner et al^Citation50	Traynor et al^Citation41	Mitchell et al^Citation51
Treatment/comparator	Riluzole/nonriluzole treated	Riluzole/nonriluzole treated	Riluzole/nonriluzole treated	Riluzole/nonriluzole treated	Riluzole/nonriluzole treated
Design	Retrospective investigation on riluzole-treated vs. nontreated patients	Retrospective investigation on riluzole-treated vs. nontreated patients	Prospective investigation of therapeutic interventions including riluzole	Retrospective investigation on riluzole-treated vs. nontreated patients	Retrospective investigation on riluzole-treated vs. nontreated patients
Country of database origin (database range – years)	ALS database – source not reported (non–treated 1989–1991; treated 1995–1997)	ALS database – North America (Wisconsin) (disease onset before [<] or from [≥] 1996)	ALS database – Kings College, UK (1990–2000)	ALS database – Republic of Ireland (1996–2000)	ALS database – Preston, UK (1980–2003)
No. patients: (total) nontreated/riluzole	(517) 161/356	<1996 (292) 241/51; ≥1996 (177) 65/112	(656) 349/299	(246) 97/149	(475) 327/148
Median survival time (with 95% CI if given) in overall ALS patient population: nontreated/riluzole [tracheostomy-free survival unless otherwise stated]	12.4 months/18.4 months p<0.001 (log-rank); survival from time of diagnosis	<1996: 47.7 (38.3–67)/58.4 (47.3–>67) months p=0.1338 (log–rank); ≥1996: 49.1 (38.1–67)/>67 (>67–>67) months p=0.0438; survival from time of symptom onset	32 (29–35)/51 (43–59) months p<0.0001 (log–rank); survival from time of symptom onset	10.1/14.3 months; survival from time of diagnosis (p=0.32 log-rank; p=0.015 Peto-test)a	2.25 (2.03–2.48)/3.07 (2.73–3.41) years; survival from time of onset; difference in median survival times (with 95% CI) for non–treated: HR 1.66 (1.32–2.12) p<0.05 (log-rank)
Cox regression analysis for riluzole treated (unless otherwise specified): RR or HR (with 95% CI) if reported	NR	Riluzole use a significant prognostic factor p<0.0001	RR 0.48 p<0.0001	HR for untreated 1.08 (0.78–1.48) p=0.64	HR for riluzole-treated 0.20 (0.089–0.46) p<0.001
Parameters	Zoccolella et al^Citation52	Lee et al^Citation53	Georgoulopoulou et al^Citation54	Knibb et al^Citation55	Chen et al^Citation56
Treatment/comparator	Riluzole/nonriluzole treated	Riluzole/nonriluzole treated	Riluzole/nonriluzole treated	Riluzole/nonriluzole treated	Riluzole/nonriluzole treated
Design	Prospective investigation on riluzole-treated vs. nontreated patients	Retrospective population-based investigation on the effect of various factors including riluzole	Prospective investigation on clinical and therapeutic interventions including riluzole	Prospective investigation on clinical and therapeutic interventions including riluzole	Prospective population-based investigation on the effect of various factors including riluzole
Database source	ALS database – Puglia, Italy (1998–1999)	ALS database – Taiwan (1999–2008)	ALS database – Modena, Italy (2000–2009)	ALS database – South East, UK (1990–2013)	ALS database – China (2007–2013)
No. patients: (total) nontreated/riluzole	(126) 53/73	(1,149) 451/698	(193) 60/133	(575) 315/260	(1,540) 1,125/415
Median survival time (with 95% CI if given) in overall ALS patient population: nontreated/riluzole [tracheostomy-free survival unless otherwise stated]	12.4 (0.3-50)/18.3 (1.8-48) months; (p=0.78 log-rank; p=0.09 Peto-test)a survival from time of diagnosis	Survival from time of diagnosis; NR (textual description only)	Univariate analysis 31 (25–46)/38 (35–43) months p=0.11 (log-rank); corresponding survival time to death: 31 (25–46)/43 (37–51) months p<0.01; survival time from symptom onset	Time from diagnosis to respiratory involvement: coefficient for riluzole use: 0.328 (0.15–0.51) p<0.001 (log-rank) in bulbar onset patients; 0.408 (0.22–0.60) p<0.0001 in limb onset patients	64.0 (57.8–70.2)/67.0 (54.7–79.3) months p=0.780 (log-rank).
Cox regression analysis for riluzole treated (unless otherwise specified): RR or HR (with 95% CI) if reported	RR 0.51 (0.25–1.03) p<0.06	Unadjusted HR 0.32 (0.22–0.45) p<0.001; adjusted HR for riluzole-treated 0.34 (0.24–0.49) p<0.001	Stratified analysis median survival times (nontreated/treated) in overall population: diagnosis <2006: 31/46 p=0.16 (log-rank); diagnosis ≥2006: 26/36 p=0.21; Cox analysis revealed riluzole treatment was independently related to longer survival (p<0.01)	Time from diagnosis to respiratory involvement: coefficient: 0.228 (0.077–0.380) p=0.003 in bulbar onset patients; 0.205 (0.057–0.353) p=0.006 in limb onset patients	HR 0.855 (0.685–1.068) p=0.167 Subgroups:b HR >Q3 0.488 (0.320–0.746) p=0.001

Notes:

a A significant difference between survival data was not demonstrable based on the log-rank sum test (applies equal weight across all events) but was observed (or demonstrated a trend toward significance) using the Peto-test, which compares the early part of the survival curves.

b Most significant results based on subgroup analyses. Subgroups based on cDDD: quartile 1 (Q1) 2,800 mg; quartile 3 (Q3) 16,800 mg. Improvement in survival observed for >Q3 vs. control, vs. <Q1 (p=0.001) and vs. ≥Q1–≤Q3 (p=0.0005).

Abbreviations: ALS, amyotrophic lateral sclerosis; cDDD, cumulative defined daily dose; CI, confidence interval; HR, hazard ratio; NA, not applicable; NP, not performed; NR, not reported; RCT, randomized controlled trial; RR, relative risk.

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