Table 2.
Summary of survival outcomes based on real-world evidence on riluzole in ALS patients
| Parameters | Meininger et al48 | Brooks et al49 | Turner et al50 | Traynor et al41 | Mitchell et al51 |
|---|---|---|---|---|---|
| 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 al52 | Lee et al53 | Georgoulopoulou et al54 | Knibb et al55 | Chen et al56 |
| 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.