Gavin Giovannoni, 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, Licínio Craveiro, Caroline Giacobino, Marianna Manfrini, Hans‐Martin Schneble, Paula Stevenson, Qing Wang, Ke Yang, Jiwon Oh, Michael Barnett, Christopher Dwyer, Richard Macdonell, Mark Marriott, Marion Simpson, Veronica Popescu, Vincent Van Pesch, Barbara Willekens, Hristo Lilovski, Ivan Milanov, Plamen Tsvetanov, Alexander MacDougall, James J. Marriott, John Roger McKelvey, Jiwon Oh, Michael Thorne, Reza Vosoughi, Carlos Navas, César Franco Ruiz, Mario Habek, Vanja Bašić Kes, Spomenka Kidjemet -Piskac, Laura Airas, Giovanni Castelnovo, Pierre Clavelou, Jerome De Seze, David Laplaud, Guillaume Mathey, Aurélie Ruet, Maia Beridze, Marina Janelidze, Alexander Tsiskaridze, Roberto Bergamaschi, Giancarlo Comi, Massimo Filippi, Luigi Grimaldi, Matilde Inglese, Giacomo Lus, Simona Malucchi, Girolama Alessandra Marfia, Carlo Pozzilli, Giovanni Ristori, Antonio Uccelli, Halim Abboud, Aline Mourad, Freddy Guillermo Castro Farfan, Elmer Guillermo López Meza, Marco Martinez Gurrola, Carlos Martinez-Manzanera, Verónica Rivas, Daniel San Juan Orta, Najib Kissani, Nissrine Louhab, Wafa Regragui, Deborah Mason, John Mottershead, Halina Bartosik-Psujek, Robert Bonek, Urszula Chyrchel-Paszkiewicz, Maciej Czarnecki, Waldemar Fryze, Elżbieta Jasińska, Alina Kułakowska, Maciej Maciejowski, Stanisław Ochudło, Marcin Ratajczak, Konrad Rejdak, Krzysztof Selmaj, Agnieszka Slowik, Karolina Piasecka Stryczynska, Monika Susz-Kolodynska, Maciej Świat, Marzena Tomaszewska, Andrzej Tutaj, Janusz Zbrojkiewicz, Tomasz Zieliński, João Cerqueira
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.