Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis
Bibliographic record
Abstract
BACKGROUND: Throughout the course of multiple sclerosis, gradually progressive neurologic impairment can occur, which has been called disability accrual. Current disease-modifying therapies for multiple sclerosis have limited effects on disability accrual unrelated to relapses, which is thought to be partially caused by chronic, nonresolving neuroinflammation within the central nervous system. Tolebrutinib is an oral, brain-penetrant Bruton's tyrosine kinase inhibitor that targets myeloid cells (including microglia) and B cells in both the periphery and central nervous system. There are no approved treatments for nonrelapsing secondary progressive multiple sclerosis. METHODS: In a phase 3, double-blind, placebo-controlled, event-driven trial, we randomly assigned participants with nonrelapsing secondary progressive multiple sclerosis, in a 2:1 ratio, to receive tolebrutinib (60 mg once daily) or matching placebo. The primary end point was confirmed disability progression that was sustained for at least 6 months, assessed in a time-to-event analysis. RESULTS: A total of 1131 participants underwent randomization: 754 were assigned to receive tolebrutinib and 377 to receive placebo. The median follow-up was 133 weeks. A smaller percentage of participants in the tolebrutinib group than in the placebo group had confirmed disability progression sustained for at least 6 months (22.6% vs. 30.7%; hazard ratio, 0.69; 95% confidence interval, 0.55 to 0.88; P = 0.003). Serious adverse events occurred in 15.0% of the participants in the tolebrutinib group and in 10.4% of those in the placebo group. A total of 4.0% of the participants in the tolebrutinib group and 1.6% of those in the placebo group had increases in alanine aminotransferase levels to more than 3 times the upper limit of the normal range. CONCLUSIONS: In participants with nonrelapsing secondary progressive multiple sclerosis, the risk of disability progression was lower among those who received treatment with tolebrutinib than among those who received placebo. (Funded by Sanofi; HERCULES ClinicalTrials.gov number, NCT04411641.).
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.005 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".