Ludwig Kappos, Sean Yiu, Jason Reucassel, Jiwon Oh, Cristina Granziera, Joep Killestein, Robert A. Bermel, Claude Berge, Agne Kazlauskaite, Hans-Martin Schneble, Frank Dahlke, Bruce A. C. Cree
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Cree","doi":"10.1002/acn3.70111","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Objective</h3>\n \n <p>The characteristics and utility of composite progression independent of relapse activity (cPIRA; worsening on the Expanded Disability Status Scale [EDSS], or 9-Hole Peg Test, or Timed 25-Foot Walk Test) were evaluated as an endpoint in relapsing multiple sclerosis (RMS) trials using the ENSEMBLE (NCT03085810) and pooled OPERA I/II (NCT01247324/NCT01412333) studies.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>We evaluated: (i) different definitions and the impact of rebaselining post-relapse on cPIRA, (ii) cPIRA and biomarkers (MRI activity and serum neurofilament light [sNfL] levels), (iii) sustainability of cPIRA events, and (iv) cPIRA impact on future outcomes, in patients treated with ocrelizumab (600 mg, OPERA I/II [<i>n</i> = 827] and ENSEMBLE [<i>n</i> = 1225]) or interferon β-1a (44 μg, OPERA I/II [<i>n</i> = 829]).</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Low disease activity (relapses/new MRI lesions) rendered rebaselining unnecessary for cPIRA status in > 95% of ocrelizumab-treated participants, and variations of cPIRA definitions yielded similar event rates. In OPERA I/II and ENSEMBLE ocrelizumab arms, cPIRA events were independent of MRI activity (86.5% and 95.5%, respectively), and occurred when sNfL was low (risk of cPIRA, hazard ratio [HR]: 0.67; <i>p</i> = 0.11 and 0.57; <i>p</i> = 0.003); more cPIRA events were sustained until study end with interferon β-1a (80.3% OPERA I/II) vs. ocrelizumab (63.2% OPERA I/II, 56.6% ENSEMBLE). Across studies and treatments, cPIRA was associated with an increased risk of subsequent worsening on the EDSS (HR, 1.62–1.74; <i>p</i> = 0.121–0.037), Symbol Digit Modalities Test (HR, 1.16–2.62; <i>p</i> = 0.54–0.009), and Multiple Sclerosis Impact Scale-29 physical scale (HR, 1.76; <i>p</i> = 0.064).</p>\n </section>\n \n <section>\n \n <h3> Interpretation</h3>\n \n <p>cPIRA is clinically relevant and demonstrates utility as a sensitive endpoint in MS clinical trials.</p>\n </section>\n \n <section>\n \n <h3> Trial Registration</h3>\n \n <p>ClinicalTrials.gov identifiers: OPERA I (NCT01247324; https://clinicaltrials.gov/study/NCT01247324); OPERA II (NCT01412333; https://clinicaltrials.gov/study/NCT01412333); ENSEMBLE (NCT03085810; https://clinicaltrials.gov/study/NCT03085810)</p>\n </section>\n </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"12 9","pages":"1805-1812"},"PeriodicalIF":3.9000,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/acn3.70111","citationCount":"0","resultStr":"{\"title\":\"Performance of Composite Endpoints Defining Progression Independent of Relapse Activity in Multiple Sclerosis\",\"authors\":\"Ludwig Kappos, Sean Yiu, Jason Reucassel, Jiwon Oh, Cristina Granziera, Joep Killestein, Robert A. 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引用次数: 0
摘要
目的：独立于复发活动的复合进展（cPIRA）的特点和应用；在使用ENSEMBLE （NCT03085810）和合并OPERA I/II （NCT01247324/NCT01412333）研究的复发性多发性硬化症（RMS）试验中，对扩展残疾状态量表（EDSS）、9孔Peg测试或计时25英尺步行测试的恶化进行了评估。方法：我们评估：(i)不同的定义和复发后重新基线对cPIRA的影响，（ii） cPIRA和生物标志物（MRI活性和血清神经丝光[sNfL]水平），（iii） cPIRA事件的可持续性，以及（iv） cPIRA对未来结局的影响，在接受ocrelizumab （600 mg, OPERA i / ii [n = 827]和ENSEMBLE [n = 1225]）或干扰素β-1a （44 μg, OPERA i / ii [n = 829]）治疗的患者中。结果：低疾病活动性（复发/新的MRI病变）使得95%的ocrelizumab治疗参与者无需重新基线检测cira状态，并且cira定义的变化产生相似的事件发生率。在OPERA I/II和ENSEMBLE ocrelizumab组中，cira事件独立于MRI活性（分别为86.5%和95.5%），并且发生在sNfL较低时(cira风险，风险比[HR]: 0.67；P = 0.11和0.57；p = 0.003)；干扰素β-1a （80.3% OPERA I/II）与ocrelizumab （63.2% OPERA I/II, 56.6% ENSEMBLE）相比，更多的cira事件持续到研究结束。在研究和治疗中，cira与EDSS随后恶化的风险增加相关(HR, 1.62-1.74；p = 0.121-0.037)，符号数字模态测试(HR, 1.16-2.62；p = 0.54-0.009)，多发性硬化症影响量表-29物理量表(HR, 1.76；p = 0.064)。解释：cpia具有临床相关性，并且在MS临床试验中作为一个敏感终点具有实用性。试验注册：ClinicalTrials.gov标识符：OPERA I (NCT01247324；https://clinicaltrials.gov/study/NCT01247324);Opera ii (nct01412333；https://clinicaltrials.gov/study/NCT01412333);合奏(NCT03085810;https://clinicaltrials.gov/study/NCT03085810)。
Performance of Composite Endpoints Defining Progression Independent of Relapse Activity in Multiple Sclerosis
Objective
The characteristics and utility of composite progression independent of relapse activity (cPIRA; worsening on the Expanded Disability Status Scale [EDSS], or 9-Hole Peg Test, or Timed 25-Foot Walk Test) were evaluated as an endpoint in relapsing multiple sclerosis (RMS) trials using the ENSEMBLE (NCT03085810) and pooled OPERA I/II (NCT01247324/NCT01412333) studies.
Methods
We evaluated: (i) different definitions and the impact of rebaselining post-relapse on cPIRA, (ii) cPIRA and biomarkers (MRI activity and serum neurofilament light [sNfL] levels), (iii) sustainability of cPIRA events, and (iv) cPIRA impact on future outcomes, in patients treated with ocrelizumab (600 mg, OPERA I/II [n = 827] and ENSEMBLE [n = 1225]) or interferon β-1a (44 μg, OPERA I/II [n = 829]).
Results
Low disease activity (relapses/new MRI lesions) rendered rebaselining unnecessary for cPIRA status in > 95% of ocrelizumab-treated participants, and variations of cPIRA definitions yielded similar event rates. In OPERA I/II and ENSEMBLE ocrelizumab arms, cPIRA events were independent of MRI activity (86.5% and 95.5%, respectively), and occurred when sNfL was low (risk of cPIRA, hazard ratio [HR]: 0.67; p = 0.11 and 0.57; p = 0.003); more cPIRA events were sustained until study end with interferon β-1a (80.3% OPERA I/II) vs. ocrelizumab (63.2% OPERA I/II, 56.6% ENSEMBLE). Across studies and treatments, cPIRA was associated with an increased risk of subsequent worsening on the EDSS (HR, 1.62–1.74; p = 0.121–0.037), Symbol Digit Modalities Test (HR, 1.16–2.62; p = 0.54–0.009), and Multiple Sclerosis Impact Scale-29 physical scale (HR, 1.76; p = 0.064).
Interpretation
cPIRA is clinically relevant and demonstrates utility as a sensitive endpoint in MS clinical trials.
Trial Registration
ClinicalTrials.gov identifiers: OPERA I (NCT01247324; https://clinicaltrials.gov/study/NCT01247324); OPERA II (NCT01412333; https://clinicaltrials.gov/study/NCT01412333); ENSEMBLE (NCT03085810; https://clinicaltrials.gov/study/NCT03085810)
期刊介绍：
Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.
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