Journal Article Multicenter Study Clinical Trial, Phase III Randomized Controlled Trial Ppublish 1 citation
PubMed: 42208561 DOI: 10.1016/S0140-6736(26)00617-3
Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis, including older patients and those with more advanced disease (ORATORIO-HAND): a multicentre, double-blind, randomised, placebo-controlled, phase 3b study.
Lancet 407(10544):2195-2207
Authors: Gavin Giovannoni, Laura Airas, Riley Bove, Gary R Cutter, Maciej Czarnecki, Jelena Drulovic, Jeremy Hobart, Jens Kuhle, Xavier Montalban, Krzysztof W Selmaj, Carmen Tur, Jerry S Wolinsky, Anna Baldinotti, Ulrike Bonati, Licinio Craveiro, Caroline Giacobino, Marianna Manfrini, Hans-Martin Schneble, Paula Stevenson, Qing Wang, Ke Yang, Jiwon Oh
Affiliations
- Department of Neurology, Royal London Hospital, Barts Health NHS Trust, London, UK; Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.
- Clinical Neurosciences and InFLAMES Research Flagship, University of Turku, Turku, Finland; Neurocenter, Turku University Hospital, Turku, Finland.
- UCSF Weill Institute for Neuroscience, Department of Neurology, University of California San Francisco, San Francisco, CA, USA.
- University of Alabama at Birmingham, Birmingham, AL, USA.
- Centrum Medyczne NeuroProtect, Warsaw, Poland.
- University Clinical Center of Serbia and University of Belgrade, Faculty of Medicine, Belgrade, Serbia.
- Peninsula Medical School, Plymouth University, Plymouth, UK.
- MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Basel, Switzerland.
- Centre d'Esclerosi Múltiple de Catalunya, Vall d'Hebron University Hospital, Barcelona, Spain.
- University of Warmia and Mazury, Olsztyn, Lodz, Poland; Center for Neurology, Lodz, Poland.
- Queen Square MS Centre, Department of Neuroinflammation, Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK; Neurology-Neuroimmunology Department, Multiple Sclerosis Centre of Catalonia, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
- Department of Neurology, University of Texas Health Science Center, Houston, TX, USA.
- F Hoffmann-La Roche, Basel, Switzerland.
- Division of Neurology, Department of Medicine, St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
Abstract
BACKGROUND
The ORATORIO trial showed that ocrelizumab reduced the risk of disability progression versus placebo in patients with primary progressive multiple sclerosis (PPMS). We aimed to elucidate the effect of ocrelizumab in older and more disabled patients with PPMS, particularly regarding hand function preservation.
METHODS
ORATORIO-HAND was a multicentre, double-blind, randomised, placebo-controlled, phase 3b study with 138 sites across 22 countries. Patients with PPMS aged 18-65 years and Expanded Disability Status Scale (EDSS) score of 3·0-8·0 were randomly assigned 1:1 to intravenous ocrelizumab 600 mg or placebo every 6 months for 144 weeks or until a prespecified number of progression events occurred. Masking was achieved by use of a placebo solution administered in the same manner as ocrelizumab. Double-blinding across all periods was maintained through separation of investigators responsible for efficacy and safety assessments. MRI scans were evaluated by a masked central reader, and laboratory parameters that could reveal treatment allocation were masked to site personnel until the primary analysis. Two coprimary estimands were defined, with the endpoint of time to onset of 12-week composite confirmed disability progression (12W-cCDP) in 9-Hole Peg Test or EDSS evaluated in all randomly assigned patients, and the same endpoint evaluated in a subset of patients with MRI activity at baseline. This study is registered with ClinicalTrials.gov, NCT04035005 and is ongoing and not recruiting.
FINDINGS
Between Aug 12, 2019, and Dec 10, 2024, of 1360 patients assessed for eligibility, 1013 were randomly assigned (ocrelizumab [n=505]; placebo [n=508]). The proportion of patients with 12W-cCDP was 165 (33%) of 505 with ocrelizumab and 205 (40%) of 508 with placebo (hazard ratio, 95% CI 0·70 0·57-0·86; relative risk reduction=30%; p=0·0007). In the MRI-active subgroup, a significant risk reduction was also observed in 12W-cCDP (risk reduction=55%; p<0·0001). The overall safety profile was similar in both groups. More infections (245 [48%] of 506 vs 226 [45%] of 506) were observed with ocrelizumab, but not after COVID-19 was excluded (38% vs 37%). Rates of serious adverse events and serious infections were similar between groups.
INTERPRETATION
Ocrelizumab was superior to placebo in delaying disability progression, with stronger effect on hand function, in a broad PPMS population including older patients and those with more advanced disease, while maintaining a manageable safety profile.
FUNDING
F Hoffmann-La Roche.
MeSH
Sclerosis, Multiple Sclerosis, Safety, Infections, Primary Progressive Multiple Sclerosis