ORATORIO-HAND
(2026)Objective
To evaluate the efficacy and safety of ocrelizumab in a broad primary progressive multiple sclerosis (PPMS) population — including older patients (>55 years) and those with more advanced disability (EDSS >6.5) — with a particular focus on preserving upper-limb (hand) function.
Study Summary
• In the MRI-active subgroup, treatment effect was even larger with a 55% risk reduction (p<0.0001)
• Overall safety profile was similar between groups; infections were more frequent with ocrelizumab (48% vs 45%) but rates were equal after excluding COVID-19 (38% vs 37%), with similar rates of serious adverse events and serious infections
Intervention
Intravenous ocrelizumab 600 mg every 24 weeks (first dose split as two 300-mg infusions 14 days apart) for up to 144 weeks vs matched placebo.
Inclusion Criteria
Adults 18-65 years with PPMS per 2017 McDonald criteria, EDSS 3.0-8.0, documented elevated IgG index or oligoclonal bands, ability to complete 9HPT in >25 s (mean of two hands) and within 240 s with each hand, with disease duration limits: <20 yrs (EDSS 7.0-8.0), <15 yrs (EDSS 5.5-6.5), <10 yrs (EDSS ≤5.0).
Study Design
Arms: Ocrelizumab 600 mg IV every 24 weeks (n=505) vs Placebo IV every 24 weeks (n=508)
Patients per Arm: Ocrelizumab n=505; Placebo n=508
Outcome
• MRI-active subgroup: 55% risk reduction in 12W-cCDP (p<0.0001)
• Safety: infections 48% (ocrelizumab) vs 45% (placebo); equal at 38% vs 37% excluding COVID-19; serious AEs and serious infections similar between groups
Bottom Line
In a broad PPMS population including older patients and those with EDSS up to 8.0, ocrelizumab 600 mg IV every 24 weeks significantly delayed composite 12-week confirmed disability progression (9HPT or EDSS) by 30% versus placebo, with an even larger 55% risk reduction in the MRI-active subgroup, and an acceptable safety profile. These data extend ocrelizumab's therapeutic window into more advanced disease and validate the 9HPT as a clinically meaningful outcome — supporting treatment of PPMS patients beyond the EDSS 6.5 ceiling that has historically excluded them from DMTs.
Major Points
- Largest placebo-controlled PPMS trial to date enrolling patients with EDSS up to 8.0 and age up to 65 years — populations excluded from the original ORATORIO trial
- Ocrelizumab reduced the risk of 12-week composite confirmed disability progression (9HPT or EDSS) by 30% vs placebo (HR 0.70, 95% CI 0.57-0.86; p=0.0007)
- Effect was substantially larger in the MRI-active subgroup, with a 55% relative risk reduction (p<0.0001)
- Composite primary endpoint combining 9HPT with EDSS validates hand-function dexterity as a clinically meaningful, trial-quality outcome in progressive MS
- Safety profile consistent with prior ocrelizumab experience; increased infections were driven by COVID-19, with rates equalising between groups when COVID-19 was excluded (38% vs 37%)
- Findings challenge the historical EDSS 6.5 therapeutic ceiling and support intervention in more advanced PPMS
Study Design
- Study Type
- Multicentre, randomised, double-blind, placebo-controlled, event-driven, phase 3b trial
- Randomization
- Yes
- Blinding
- Double-blind; placebo solution identical in composition, configuration, and administration to ocrelizumab. Dual-assessor model separated investigators responsible for efficacy and safety assessments. MRI scans read by masked central reader. Laboratory parameters that could unblind (CD19+ counts, immunoglobulin concentrations) masked to site personnel until primary analysis.
- Sample Size
- 1013
- Follow-up
- Up to 144 weeks in double-blind treatment phase (or until ≥340 disability progression events on 9HPT or EDSS), followed by optional post-double-progression period, follow-up 1, optional open-label extension, and follow-up 2
- Centers
- 138
- Countries
- 22 countries (EU, UK, Canada, and other regions)
Primary Outcome
Definition: Time to onset of 12-week composite confirmed disability progression (12W-cCDP), defined as the first occurrence of CDP in 9HPT (≥20% worsening from baseline in time to complete 9HPT) or CDP in EDSS (≥1.0-point increase if baseline EDSS ≤5.5, or ≥0.5-point increase if baseline EDSS >5.5), sustained for ≥12 weeks. Evaluated in two coprimary estimands: all randomly assigned patients (ITT) and the MRI-active subgroup.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 205/508 (40%) with 12W-cCDP | 165/505 (33%) with 12W-cCDP | 0.7 (0.57-0.86 (ITT)) | 0.0007 (ITT); <0.0001 (MRI-active subgroup) |
Limitations & Criticisms
- Funded by manufacturer F Hoffmann-La Roche, which could introduce sponsor bias
- MRI-active subgroup coprimary estimand selectively enriches for inflammatory disease activity, which may not generalise to truly MRI-stable PPMS
- Exact baseline demographics, subgroup numerical results, and Neuro-QoL-UE findings not extracted from available text section
- Event-driven design ended at 340 progression events — long-term durability beyond 144 weeks not yet established in this analysis
Citation
Lancet 2026; 407: 2195-207