Primary efficacy endpoints analysed in two patient populations
| (A) Analysis conducted using data from all participants | |||||||
| Primary efficacy endpoints | Placebo (n=123) | Methylcobalamin | Crude p value (comparison with placebo) | Adjusted p value (comparison with placebo) | |||
| 25 mg (n=124) | 50 mg (n=123) | 50 mg | Methylcobalamin | 50 mg | Methylcobalamin | ||
| Time to the primary event*, day | |||||||
| Median (95% CI) | 880 (678 to 1217 | 1147 (819 to –) | 954 (777 to –) | 0.33† | 0.20† | 0.15† | 0.13† |
| First quartile (25%) (95% CI) | 465 (363 to 538) | 499 (392 to 610) | 503 (377 to 627) | ||||
| Third quartile (75%) (95% CI) | –‡ | ‡ | –‡ | ||||
| HR vs the placebo group in each active group (95% CI) | – | 0.83 (0.58 to 1.20) | 0.92 (0.65 to 1.32) | ||||
| HR vs the placebo group in total active group (95% CI) | – | 0.88 (0.64 to 1.20) | |||||
| Change in ALSFRS-R score | |||||||
| Patients, n | 123 | 124 | 122 | ||||
| Median (min, max) | −24.0 (−42, −1) | −22.0 (−42, 2) | −21.0 (−39, 1) | 0.15§ | 0.09§ | 0.18§ | 0.19§ |
| First quartile (25%) | −30.0 | −30.5 | −27.0 | ||||
| Third quartile (75%) | −16.0 | −12.5 | −10.0 | ||||
| (B) Analysis conducted using data from the subgroup of patients diagnosed early (≤12 months after symptom onset) | |||||
| Primary efficacy endpoints | Placebo | Methylcobalamin | P value (comparison with placebo) | ||
| 25 mg | 50 mg | 50 mg | Methylcobalamin | ||
| Time to primary event*, day | |||||
| Median (95% CI) | 570 (465 to 720) | 1087 (564 to –) | 1197 (609 to –) | 0.01† | 0.01† |
| First quartile (25%) (95% CI) | 363 (201 to 491) | 410 (304 to 594) | 448 (337 to 1062) | ||
| Third quartile (75%) (95% CI) | 925 (709 to –) | – (1186) | – (–, –)¶ | ||
| HR vs the placebo group in each active group (95% CI) | 0.64 (0.38 to 1.09) | 0.50 (0.27 to 0.93) | |||
| HR vs the placebo group in total active group (95% CI) | 0.57 (0.35 to 0.92) | ||||
| Change in ALSFRS-R score | |||||
| Patients, n | 48 | 54 | 41 | ||
| Median (min, max) | −26.5 (−40, −3) | −26.5 (−40, 0) | −22.0 (−38, 1) | 0.003§ | 0.01§ |
| First quartile (25%) | −32.5 | −32.0 | −27.0 | ||
| Third quartile (75%) | −20.0 | −19.0 | −9.0 | ||
*Primary events defined as death for any cause or invasive or non-invasive ventilation support for ≥22 hours due to ALS progression.
†Intergroup difference analysed using log-rank score.
‡Third quartile of the primary event-free survival was not calculable in any of the groups.
§Intergroup difference analysed using Wilcoxon score.
¶Third quartile of time to the primary event was not calculable in the 50 mg methylcobalamin group.
ALS, amyotrophic lateral sclerosis; ALSFRS-R, Revised ALS Functional Rating Scale.