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.

We aimed to elucidate the effect of ocrelizumab in older and more disabled patients with PPMS, particularly regarding hand function preservation.

我们旨在阐明奥克珠单抗对年龄较大、残疾程度较高的原发性进展型多发性硬化症（PPMS）患者的影响，特别是关于手功能保护的效果。

Methods

ORATORIO-HAND was a multicentre, double-blind, randomised, placebo-controlled, phase 3b study with 138 sites across 22 countries.

ORATORIO-HAND 是一项多中心、双盲、随机、安慰剂对照的3b期临床试验，涉及22个国家的138个研究地点。

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.

年龄在18-65岁之间的原发进展型多发性硬化症（PPMS）患者，扩展残疾状态量表（EDSS）评分为3.0-8.0，按1:1的比例随机分配接受每6个月静脉注射600毫克的奥克雷珠单抗或安慰剂，持续144周或直到达到预设的疾病进展事件数量。

Masking was achieved by use of a placebo solution administered in the same manner as ocrelizumab.

通过使用与奥瑞珠单抗相同方式给药的安慰剂溶液来实现盲法。

Double-blinding across all periods was maintained through separation of investigators responsible for efficacy and safety assessments.

通过将负责疗效和安全性评估的研究者分开，保持了所有期间的双盲。

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.

MRI扫描由一名蒙面的中心阅片员进行评估，可能揭示治疗分配的实验室参数在主要分析完成前对现场人员保密。

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.

定义了两个共同的主要估计量，终点为在所有随机分配的患者中出现12周复合确认残疾进展（12W-cCDP）的时间，通过9孔钉板测试或EDSS进行评估，以及在基线时有MRI活动的患者子集中评估相同的终点。

This study is registered with ClinicalTrials.gov, NCT04035005 and is ongoing and not recruiting.

该研究已在ClinicalTrials.gov注册，编号NCT04035005，目前正在进行中，但不再招募新患者。

Results

Between Aug 12, 2019, and Dec 10, 2024, of 1360 patients assessed for eligibility, 1013 were randomly assigned (ocrelizumab [n=505]; placebo [n=508]).

在2019年8月12日至2024年12月10日期间，共有1360名患者接受了资格评估，其中1013名患者被随机分配（奥克雷珠单抗[n=505]；安慰剂[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).

在12周持续临床残疾进展（12W-cCDP）的患者中，接受奥瑞珠单抗的505名患者中有165名（33%），而接受安慰剂的508名患者中有205名（40%）（风险比，95%置信区间0.70，0.57-0.86；相对风险降低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).

在MRI活跃的亚组中，12周持续临床残疾进展（12W-cCDP）的风险也显著降低（风险降低55%；p<0.0001）。

The overall safety profile was similar in both groups.

两组的整体安全性特征相似。

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%).

与对照组相比，观察到更多感染病例（506名患者中有245例[48%]，而对照组为226例[45%]），但在排除COVID-19后，感染率相似（分别为38%和37%）。

Rates of serious adverse events and serious infections were similar between groups.

两组之间严重不良事件和严重感染的发生率相似。

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.

在包括老年患者和疾病进展更严重的广泛原发性进展型多发性硬化症（PPMS）人群中，奥克雷珠单抗在延缓残疾进展方面优于安慰剂，对手功能的影响更强，同时保持了可控的安全性。

funding

F Hoffmann-La Roche.

F Hoffmann-La Roche 公司。