Rationale for EDSS-Plus, the Primary Composite Endpoint of Disability Progression in the ASCEND Phase 3 Study of Natalizumab for Secondary Progressive Multiple Sclerosis: A Post Hoc Analysis of IMPACT Study Data (P7.240)
Bibliographic record
Abstract
OBJECTIVE: Present rationale for a primary composite endpoint of disability progression in secondary progressive multiple sclerosis (SPMS) clinical trials. BACKGROUND: While the Expanded Disability Status Scale (EDSS) has wide scientific/regulatory precedent, it has limited ability to detect clinically relevant disability progression in SPMS patients and lacks measures of upper extremity and short-distance ambulatory function. Previously, we observed that Timed 25-Foot Walk (T25FW) and 9-Hole Peg Test (9HPT) identified frequent progression events in placebo-treated subjects from IMPACT, a 2-year trial of intramuscular interferon-beta-1a in SPMS. DESIGN/METHODS: Using data from the IMPACT placebo arm, we analyzed progression on T25FW, 9HPT, and EDSS, defined as 24-week confirmed minimum worsening of 20[percnt] (T25FW, 9HPT) or 蠅1.0-point increase from baseline ≤5.5 or 蠅0.5-point increase from baseline 蠅6.0 (EDSS). A novel composite progression endpoint, “EDSS-Plus,” was defined as progression on 蠅1 of 3 components (T25FW, 9HPT, and/or EDSS). RESULTS: Data were analyzed from 216 placebo-treated subjects. After 2 years, 59.3[percnt] of subjects had 24-week confirmed disability progression on EDSS-Plus versus 24.5[percnt], 39.4[percnt], and 34.3[percnt] on EDSS, T25FW, and 9HPT, respectively. Among subjects with EDSS baseline ≤5.5 (n=111), 50.5[percnt] exhibited progression on EDSS-Plus versus 21.6[percnt], 30.6[percnt], and 26.1[percnt] on EDSS, T25FW, and 9HPT, respectively; among subjects with EDSS baseline 蠅6.0 (n=105), 68.6[percnt] exhibited progression on EDSS-Plus versus 27.6[percnt], 49.0[percnt], and 42.9[percnt] on EDSS, T25FW, and 9HPT, respectively. Over 2 years, subjects classified as T25FW and 9HPT progressors had average worsening of ~100[percnt] and ~200[percnt], respectively, greatly exceeding the minimum 20[percnt] threshold, while T25FW and 9HPT nonprogressors remained close to their baseline level. This indicates that the 24-week confirmed 蠅20[percnt] worsening threshold is useful in classifying clinically meaningful progression on T25FW and 9HPT in SPMS. CONCLUSIONS: EDSS-Plus is a sensitive, clinically meaningful endpoint to capture treatment effects on disability progression in SPMS over 2 years. Funding: Biogen Idec
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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 | 0.045 | 0.020 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.003 | 0.001 |
| Research integrity | 0.003 | 0.005 |
| Insufficient payload (model declined to judge) | 0.005 | 0.003 |
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".