Performance of Composite Endpoints Defining Progression Independent of Relapse Activity in Multiple Sclerosis
Bibliographic record
Abstract
OBJECTIVE: The characteristics and utility of composite progression independent of relapse activity (cPIRA; worsening on the Expanded Disability Status Scale [EDSS], or 9-Hole Peg Test, or Timed 25-Foot Walk Test) were evaluated as an endpoint in relapsing multiple sclerosis (RMS) trials using the ENSEMBLE (NCT03085810) and pooled OPERA I/II (NCT01247324/NCT01412333) studies. METHODS: We evaluated: (i) different definitions and the impact of rebaselining post-relapse on cPIRA, (ii) cPIRA and biomarkers (MRI activity and serum neurofilament light [sNfL] levels), (iii) sustainability of cPIRA events, and (iv) cPIRA impact on future outcomes, in patients treated with ocrelizumab (600 mg, OPERA I/II [n = 827] and ENSEMBLE [n = 1225]) or interferon β-1a (44 μg, OPERA I/II [n = 829]). RESULTS: Low disease activity (relapses/new MRI lesions) rendered rebaselining unnecessary for cPIRA status in > 95% of ocrelizumab-treated participants, and variations of cPIRA definitions yielded similar event rates. In OPERA I/II and ENSEMBLE ocrelizumab arms, cPIRA events were independent of MRI activity (86.5% and 95.5%, respectively), and occurred when sNfL was low (risk of cPIRA, hazard ratio [HR]: 0.67; p = 0.11 and 0.57; p = 0.003); more cPIRA events were sustained until study end with interferon β-1a (80.3% OPERA I/II) vs. ocrelizumab (63.2% OPERA I/II, 56.6% ENSEMBLE). Across studies and treatments, cPIRA was associated with an increased risk of subsequent worsening on the EDSS (HR, 1.62-1.74; p = 0.121-0.037), Symbol Digit Modalities Test (HR, 1.16-2.62; p = 0.54-0.009), and Multiple Sclerosis Impact Scale-29 physical scale (HR, 1.76; p = 0.064). INTERPRETATION: cPIRA is clinically relevant and demonstrates utility as a sensitive endpoint in MS clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: OPERA I (NCT01247324; https://clinicaltrials.gov/study/NCT01247324); OPERA II (NCT01412333; https://clinicaltrials.gov/study/NCT01412333); ENSEMBLE (NCT03085810; https://clinicaltrials.gov/study/NCT03085810).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.030 | 0.019 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.003 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".