Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study
Notice bibliographique
Résumé
BackgroundRiluzole is the only drug to prolong survival for amyotrophic lateral sclerosis (ALS) and, at a dose of 100 mg, was associated with a 35% reduction in mortality in a clinical trial. A key question is whether the survival benefit occurs at an early stage of disease, late stage, or is spread throughout the course of the disease. To address this question, we used the King's clinical staging system to do a retrospective analysis of data from the original dose-ranging clinical trial of riluzole.MethodsIn the original dose-ranging trial, patients were enrolled between December, 1992, and November, 1993, in Belgium, France, Germany, Spain, Canada, the USA, and the UK if they had probable or definite ALS as defined by the El Escorial criteria. The censor date for the riluzole survival data was set as the original study end date of Dec 31, 1994. For this analysis, King's clinical ALS stage was estimated from the electronic case record data of the modified Norris scale, UK Medical Research Council score for muscle strength, El Escorial category, vital capacity, and gastrostomy insertion data. The lowest allocated stage was 2 because the original trial only included patients with probable or definite ALS. We used a χ2 test to assess the independence of stage at trial enrolment and treatment group, Kaplan-Meier product limit distribution to test the transition from each stage to subsequent stages, and Cox regression to confirm an effect of treatment group on time in stage, controlling for covariates. We did sensitivity analyses by combining treatment groups, using alternative strategies to stage, stratifying by stage at trial enrolment, and using multistate outcome analysis of treatments (MOAT).FindingsWe analysed the case records of all 959 participants from the original dose-ranging trial, 237 assigned to 50 mg/day riluzole, 236 to 100 mg/day, 244 to 200 mg/day, and 242 to daily placebo. Clinical stage at enrolment did not significantly differ between treatment groups (p=0·22). Time in stage 4 was longer for patients receiving 100 mg/day riluzole than for those receiving placebo (hazard ratio [HR] 0·55, 95% CI 0·36–0·83; log-rank p=0·037). Combining treatment groups and stratifying by stage at enrolment showed a similar result (HR 0·638, 95% CI 0·464–0·878; p=0·006), as did analysis with MOAT where the mean number of days spent in stage 4 was numerically higher for patients given riluzole at higher doses compared with patients receiving placebo. Time from stages 2 or 3 to subsequent stages or death did not differ between riluzole treatment groups and placebo (p=0·83 for stage 2 and 0·88 for stage 3).InterpretationWe showed that riluzole prolongs survival in the last clinical stage of ALS; this finding needs to be confirmed in a prospective study, and treatment effects at stage 1 still need to be analysed. The ALS stage at which benefit occurs is important for counselling of patients before starting treatment. Staging should be used in future ALS clinical trials to assess the stage at which survival benefit occurs, and a similar approach could be used for other neurodegenerative diseases.FundingNIHR Maudsley Biomedical Research Centre, The European Union Joint Programme on Neurodegeneration, and the King's Summer Undergraduate Studentship.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».