Received: 3 December 2020 | Accepted: 11 March 2021 DOI: 10.1111/ene.14824 ORIGINAL ARTICLE Risk of requiring a wheelchair in primary progressive multiple sclerosis: Data from the ORATORIO trial and the MSBase registry Helmut Butzkueven1 | Tim Spelman2 | Dana Horakova3 | Stella Hughes4,5 | Claudio Solaro6 | Guillermo Izquierdo7 | Eva Kubala Havrdová8 | Francois Grand'Maison9 | Alexandre Prat10 | Marc Girard10 | Raymond Hupperts11 | Marco Onofrj12 | Alessandra Lugaresi13,14 | Bruce Taylor15 | the MSBase Study Group | Gavin Giovannoni16 | Ludwig Kappos17 | Stephen L. Hauser18 | Xavier Montalban19 | Licinio Craveiro20 | Rita Freitas20 | Fabian Model20 | James Overell20 | Erwan Muros-­Le Rouzic20 | Annette Sauter20 | Qing Wang20 | David Wormser20 | Jerry S. Wolinsky21 1 Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia 2 Department of Medicine and Melbourne Brain Centre, The Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia 3 Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic 4 Department of Neurology, Craigavon Area Hospital, Craigavon, UK 5 Belfast Health and Social Care Trust, Belfast, UK 6 CRRF "Mons. Luigi Novarese", Moncrivello, (VC), Italy 7 Vithas Nisa Hospital, Seville, Spain 8 Department of Neurology and Center of Clinical Neuroscience, General University Hospital and Charles University, Prague, Czech Republic 9 Neuro Rive-­Sud, Quebec City, Quebec, Canada 10 CHUM and Universite de Montreal, Montreal, Quebec, Canada 11 Zuyderland Ziekenhuis, Sittard, The Netherlands 12 University G. d'Annunzio, Chieti, Italy 13 IRCCS Istituto delle Scienze Neurologiche di Bologna, UOSI Riabilitazione Sclerosi Multipla, Bologna, Italy 14 Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy 15 Royal Hobart Hospital, Hobart, Tasmania, Australia 16 Queen Mary University of London, London, UK 17 Research Center for Clinical Neuroimmunology and Neuroscience and MS Center, University Hospital Basel and University of Basel, Basel, Switzerland 18 University of California, San Francisco, California, USA 19 Department of Neurology–­Neuroimmunology, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Barcelona, Spain 20 F. Hoffmann–­L a Roche Ltd, Basel, Switzerland 21 McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA Correspondence Helmut Butzkueven, Department of Neuroscience, Central Clinical School, Monash University, The Alfred Centre, Level 6, 99 Commercial Road, Melbourne, Vic 3004, Australia. Email: helmut.butzkueven@monash.edu Present address During completion of the work related to this manuscript, R.Frietas was an employee of F.Hoffman-La Roche Ltd; her current affiliation is Novartis Pharma AG During completion of the work related to this manuscript, D.Wormser was an employee of F.Hoffman-La Roche Ltd; his current affiliation is Novartis, Basel, Switzerland This is an open access article under the terms of the Creative Commons Attribution-­NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology Eur J Neurol. 2021;00:1–9.  wileyonlinelibrary.com/journal/ene | 1 2 | BUTZKUEVEN et al. Funding information Abstract This work was financially supported by F. Hoffmann-­L a Roche Ltd., Basel, Background and purpose: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 repre- Switzerland for the study and publication sents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on of the article. time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-­blind and extended con- trolled periods (DBP+ECP), (ii) quantify likely long-­term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real-­world cohort (MSBase registry; ACTRN12605000455662). Methods: Post hoc analyses assessing time to 24-­week confirmed EDSS ≥7.0 in two co- horts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0–­6.5) were investigated in ORATORIO and MSBase. Results: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-­week con- firmed EDSS ≥7.0 (hazard ratio = 0.54, 95% confidence interval [CI]: 0.31–­0.92; p = 0.022). Extrapolated median time to 24-­week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1-­year delay [95% CI: −4.3 to 18.4]). In MSBase, the median time to 24-­week confirmed EDSS ≥7.0 was 12.4 years. Conclusions: Compared with placebo, ocrelizumab significantly delayed time to 24-­week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-­world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence. KEYWORDS disease progression, ocrelizumab, primary progressive multiple sclerosis, wheelchair (32.9%) versus placebo (39.3%; hazard ratio [HR] = 0.76; 95% con- I NTRO D U C TI O N fidence interval [CI]: 0.59–­0 .98; p = 0.03) [8]. In the present anal- ysis, we assessed the effect of ocrelizumab on time to EDSS ≥7.0 Approximately 10% to 15% of the multiple sclerosis (MS) population in the double-­b lind period (DBP) and extended controlled period are classified as primary progressive MS (PPMS) [1]. PPMS is distin- (ECP) of ORATORIO, and extrapolated the potential long-­term im- guished from more common relapsing forms of MS (i.e., relapsing–­ pact of ocrelizumab on time to requiring a wheelchair. We further remitting MS and secondary progressive MS) by gradual worsening assessed the plausibility of the extrapolations, using an indepen- of neurological disability from disease onset [1]. Long-­term disability dent real-­world PPMS cohort from the MSBase registry [9] along is an important outcome for patients with MS [2], and is typically with current observed data from the ongoing ORATORIO open-­ characterized using the Expanded Disability Status Scale (EDSS) [3]. label extension (OLE) [10]. Reaching EDSS ≥7.0 is a key clinical disability milestone, as this rep- resents an inability to walk >5 meters, even with an aid, essentially leading to the requirement for a wheelchair. Progression to EDSS M E TH O D S ≥7.0 is associated with a major reduction in patients' quality of life and a treatment cost increase [4]. ORATORIO trial design and patients Ocrelizumab is a humanized monoclonal antibody that selec- tively targets CD20 + B cells, while preserving the capacity for ORATORIO was a Phase III, randomized, parallel-­g roup, double-­ B-­cell reconstitution and preexisting humoral immunity [5,6]. blind, placebo-­controlled trial investigating the efficacy and Ocrelizumab is the first CD20+ B-­cell–­s elective monoclonal an- safety of ocrelizumab in patients with PPMS [8]. Key eligibility tibody approved for the treatment of relapsing MS and PPMS at criteria included age 18 to 55 years, PPMS diagnosis (2005 re- a twice-­yearly dose of 600 mg intravenously [7]. In the Phase III vised McDonald criteria [11]), and an EDSS score of 3.0 to 6.5 ORATORIO study (NCT01194570) [8] in patients with PPMS, the at screening. ORATORIO consists of three treatment periods: the proportion of patients with 12-­week confirmed disability progres- DBP (≥120 weeks), the ECP (3–­9 months; the ECP provided ap- sion (primary endpoint) was lower in patients receiving ocrelizumab proximately 3 additional months of blinded controlled data and RISK OF REQUIRING A WHEELCHAIR IN PPMS | 3 6 months of controlled follow-­u p, during which patients were superimposed onto the Weibull analysis extrapolation from the gradually unblinded and entered the OLE period), and the cur- ORATORIO placebo arm. rently ongoing OLE period. All patients completing DBP and ECP were eligible to enter the OLE period. In the ORATORIO DBP+ECP, which lasted approximately 3 years, post hoc analysis Trial registration was carried out to assess the time to onset of 24-­week confirmed EDSS ≥7.0. Consistent with the original analyses [8], patients with The ORATORIO trial was registered in the ClinicalTrials. an initial disability progression who discontinued treatment early gov registry (NCT01194570). MSBase registry was regis- and did not have a subsequent EDSS measurement were imputed tered in the Australian New Zealand Clinical Trials Registry as having a 24-­week confirmed disability progression event. To (ACTRN12605000455662). further characterize the potential long-­term impact of ocreli- zumab treatment on the time to 24-­week confirmed EDSS ≥7.0, a Weibull regression analysis [12] was used to extrapolate observed R E S U LT S data from the ORATORIO DBP+ECP into the future, estimating the time at which 50% of patients were expected to have reached Patient disposition, demographics, and characteristics EDSS ≥7.0. The distribution of survival times was approximated by the Weibull distribution, which allows for monotonically increas- Baseline characteristics from the ORATORIO DBP (n = 732) have ing or decreasing hazard rates over time [12]. We performed sen- been reported previously [8] and are summarized in Table 1. Baseline sitivity analyses using various parametric functions to estimate characteristics were consistent between groups, with a median the delay in median time to requiring a wheelchair in patients EDSS of 4.5. All patients (n = 775) in MSBase were treatment-­naïve treated with ocrelizumab versus placebo; sensitivity analyses at baseline and remained untreated for most of the study. Baseline were also performed after removal of imputed events. In addition, characteristics were similar to ORATORIO DBP, with a median EDSS we analyzed the time to onset of 24-­week confirmed EDSS ≥7.0 of 4.5. Patient disposition is shown in Figure 1. In the ocrelizumab using data from the OLE period of ORATORIO in patients initially arm, 98.4% of patients who completed the DBP+ECP of ORATORIO randomized to ocrelizumab (6 years total follow-­u p [312 weeks]) transitioned into the OLE phase (n/N = 367/373; this represents [10] to provide support for the extrapolation of the ORATORIO 75.2% of those initially randomized (n/N = 367/488). DBP+ECP ocrelizumab arm. The ORATORIO trial protocol (NCT01412333)[8] was approved by the relevant institutional review boards/ethics committees. All Time to 24-­week confirmed EDSS ≥7.0 during the patients provided written informed consent. The trial was con- DBP+ECP ducted in accordance the Declaration of Helsinki. In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-­week confirmed EDSS ≥7.0 versus placebo by 46% (HR = 0.54, MSBase registry 95% CI: 0.31–­0.92; p = 0.02; Figure 2a). The MSBase registry (Australian New Zealand Clinical Trials Registry ID: ACTRN12605000455662) is a longitudinal, prospective, interna- Extrapolation of time to 24-­week confirmed EDSS tional, web-­based database collecting standardized clinical outcomes ≥7.0 from the DBP+ECP in patients with MS [9]. MSBase was approved by the Melbourne Health Human Research Ethics Committee and by local ethics com- In the ORATORIO DBP+ECP, the extrapolated median time to 24-­ mittees in all participating centers (or exemptions granted, accord- week confirmed EDSS ≥7.0 was 12.1 years for placebo and 19.2 years ing to local protocols). Written informed consent was provided by for ocrelizumab (Figure 2b). Similar to the placebo arm, the observed patients as required. median time to 24-­week confirmed EDSS ≥7.0 in real-­world patients Using MSBase, a real-­world cohort was created including adults with PPMS from MSBase was 12.4 years (Figure 3). Extending the (aged ≥18 years) with PPMS (2005 revised McDonald criteria [11]), observation period for time to 24-­week confirmed EDSS ≥7.0 in the a baseline EDSS score of 3.0 to 6.5 (same as ORATORIO), >2 EDSS ocrelizumab arm to include the OLE period of ORATORIO supports assessments, and no disease-­modifying therapy (DMT) use prior the extrapolation from the ORATORIO DBP+ECP for the ocreli- to diagnosis. Kaplan-­Meier analyses were used to estimate time zumab group (Figure 3). By comparing the extrapolated median time to 24-­week confirmed EDSS ≥7.0, similar to ORATORIO. Baseline to 24-­week confirmed EDSS ≥7.0 in the ORATORIO DBP+ECP for EDSS was the first recorded EDSS in the PPMS untreated state. No the placebo and ocrelizumab arms, ocrelizumab is predicted to delay imputation was done when EDSS measurements were not avail- 24-­week confirmed EDSS ≥7.0 by 7.1 years (95% CI: −4.3 to 18.4) able after the initial progression (due to loss to follow-­up, death, or versus placebo. Sensitivity analyses performed without imputation analysis data cutoff). Findings from the MSBase cohort were then indicated a similar delay of 7.5 years (data not shown). 4 | BUTZKUEVEN et al. TA B L E 1 Baseline characteristics of ORATORIO ITT the ORATORIO ITT population and the OCR 600 mg, Placebo, MSBase PPMS real-­world MSBase natural history cohort Parameter n = 488 n = 244 cohort, n = 775a Age, mean (SD), years 44.7 (7.9) 44.4 (8.3) 43.4 (10.1) Female, n (%) 237 (48.6) 124 (50.8) 437 (56.4) Time since MS symptom 6.0 (3.8–­8.7) 5.5 (3.3–­8.3) 5.8 (3.0–­10.8) onset, median (IQR), years Time since MS diagnosis, 1.6 (0.5–­4.1) 1.3 (0.5–­3.9) 0.4 (0–­3.9) median (IQR), years Score on first eligible 4.5 (3.5–­6.0)b 4.5 (3.5–­6.0)b 4.5 (3.5–­6.0)c EDSS, median (IQR) Distribution of baseline EDSS scores, n (%) 2.5 1 (0.2) 1 (0.4) 0 3.0 41 (8.4) 19 (7.8) 111 (14.3) 3.5 88 (18.0) 46 (18.9) 84 (10.8) 4.0 88 (18.0) 43 (17.6) 149 (19.2) 4.5 44 (9.0) 25 (10.2) 63 (8.1) 5.0 26 (5.3) 16 (6.6) 62 (8.0) 5.5 60 (12.3) 13 (5.3) 48 (6.2) 6.0 76 (15.6) 56 (23.0) 141 (18.2) 6.5 62 (12.7) 25 (10.2) 117 (15.1) 7.0 1 (0.2) 0 0 DMT exposure, n (%) Ever exposed in 55 (11.3) 30 (12.3) 0 (0) 2 years prebaseline Never exposed in 433 (88.7) 214 (87.7) 775 (100) 2 years prebaseline Time on DMT, mean (SD), N/A N/A 0.19 (1.04) yearsd Time between consecutive EDSS visits, months Mean (SD) 3.0 e (N/A) 3.0 e (N/A) 11.0 (23.9) Median (IQR) N/A N/A 6.8 (3.9–­12.2) Abbreviations: DMT, disease-­modifying treatment; EDSS, Expanded Disability Status Scale; IQR, interquartile range; ITT, intent to treat; MS, multiple sclerosis; N/A, not applicable; OCR, ocrelizumab; PPMS, primary progressive multiple sclerosis. a Based on the MSBase registry definition of PPMS. Patient characteristics described at first recorded EDSS visit after PPMS diagnosis. b The baseline EDSS value is the average score of the EDSS assessment at screening and Day 1 visit up to and including the date of randomization. If one of the values is missing, the non-­missing values will be used as baseline. c Baseline EDSS was the first recorded EDSS in the PPMS untreated state. d Between first and last recorded EDSS visits. e As per schedule of assessments. DISCUSSION benefit for patients with PPMS. Real-­world data from the MSBase registry show a similar disability trajectory to that extrapolated from During the DBP and ECP of the ORATORIO trial, ocrelizumab placebo-­treated patients in ORATORIO, whereas initial data from significantly reduced the risk of requiring a wheelchair by 46% the ocrelizumab arm of the ORATORIO OLE period show a similar versus placebo. Extrapolated data from the DBP+ECP suggest ocre- trajectory to the extrapolation from ocrelizumab-­treated patients lizumab treatment delays the median time to requiring a wheel- in the DBP+ECP, supporting the plausibility of these extrapola- chair by 7.1 years versus placebo, indicating a meaningful long-­term tions. Time to requiring a wheelchair is a well-­defined outcome that RISK OF REQUIRING A WHEELCHAIR IN PPMS | 5 F I G U R E 1 Patient disposition in the Withdrawn from treatment ORATORIO study period. †Forty-­seven (N = 83/244; 34.0%) patients (19.3%) entered safety follow-­up from DBP. ‡Seventy-­five patients (15.4%) Completed Entered OLE entered safety follow-­up from DBP. §One PBO DBP+ECP† phase from DBP§ patient (0.6%) completed the DBP+ECP (N = 244) (N = 161/244; (N = 160/161; 66.0%) 99.4%) but did not enter the OLE period. ¶Six Randomized 2:1 patients (1.6%) completed the DBP+ECP to double-blind treatment but did not enter the OLE period. (N = 732) DBP, double-­blind period; ECP, extended Completed Entered OLE OCR DBP+ECP‡ phase from DBP¶ controlled period; OCR, ocrelizumab; (N = 488) (N = 373/488; (N = 367/373; OLE, open-­label extension; 76.4%) 98.4%) PBO, placebo Withdrawn from treatment (N = 115/488; 23.6%) allows comparisons to be made across studies and across cohorts. baseline characteristics between the real-­life MSBase cohort and Furthermore, it is a clinically meaningful outcome for patients; high the ORATORIO trial population. However, the populations were levels of disability are associated with a number of physical, emo- comparable for demographics, time since MS symptom onset, and tional, and financial challenges, and an overall reduced quality of life median baseline EDSS scores. The distribution of EDSS 6.0 to 6.5 [4,13,14]. Delaying time to EDSS ≥7.0 may alleviate some of these at baseline was similar between all groups (28.3% in ocrelizumab, burdens. However, it is important to note that due to the restricted 33.2% in placebo, 33.3% in MSBase), further suggesting that the co- eligibility criteria for ORATORIO, patients were generally younger, horts had similar disability levels at baseline. Additionally, as there had a shorter disease duration, and had lower levels of disability than are currently no other treatments approved for PPMS, the compari- a typical population; therefore, it may be difficult to generalize these son between the placebo arm and the untreated real-­world MSBase results to a broad real-­world PPMS population. cohort remains relevant. Some patients in the MSBase cohort did One study limitation is that the extrapolations from the not remain DMT-­free after the baseline EDSS assessment. However, ORATORIO DBP+ECP are based on relatively short observed off-­label DMT usage remained low, with only 49/775 patients (6.3%) periods, limiting the precision of the long-­term extrapolation. initiating DMTs and a mean of 0.19 years of DMT use between the Furthermore, the extrapolations are based on the assumption that first and last recorded EDSS visits. Additionally, off-­label DMT use the risk of disability progression is linear over time, which may not was not found to be effective in MSBase [15]. be the case; the disease course of MS is unpredictable and variable Ocrelizumab significantly delayed the time to requiring a wheel- across individuals. However, as the study is based specifically on pa- chair in the DBP and ECP of ORATORIO, and the extrapolated me- tients with PPMS, it is likely that the disease progression, through dian time to reach this disability milestone for the placebo group was the accumulation of clinical deficit and disability, occurs steadily similar to that observed in a real-­world MSBase cohort. Overall, the over time, characteristic of a linear model. effect of ocrelizumab in significantly delaying the time to requiring An additional limitation is that the data include the ECP of a wheelchair likely translates to a meaningful long-­term benefit for ORATORIO, in which gradual unblinding occurred; therefore, there patients with PPMS. may have been some bias introduced, for example informative cen- soring, causing results to be confounded. We cannot exclude the AC K N OW L E D G M E N T S possibility that those patients who discontinued ocrelizumab had Eleanor Foy (Articulate Science, UK) drafted the manuscript based a more severe disease course, and thus, the median time to reach on input from the authors, funded by F. Hoffmann–­L a Roche Ltd. EDSS ≥7.0 in ocrelizumab-­treated patients may be overestimated. The authors had full editorial control of the manuscript and provided However, 98.4% of patients in the ocrelizumab arm who completed final approval. The authors thank all patients, their families, and the the DBP+ECP of ORATORIO transitioned into the OLE period. This investigators who participated in the ORATORIO trial and MSBase represents 75.2% of those initially randomized (Figure 1), and the registry. low attrition rates in patients who completed the DBP reduces the possibility of selection bias. C O N FL I C T O F I N T E R E S T S Another limitation of this study is that the ORATORIO and H.B.'s institution (Monash University) has received funding from MSBase populations could not be directly matched for baseline Biogen, F. Hoffmann-­L a Roche Ltd., Merck. and Novartis; has carried covariate differences. The MSBase cohort was instead restricted out contracted research for Novartis, Merck, F. Hoffmann-­L a Roche to patients with the same EDSS eligibility criteria as ORATORIO. Ltd., and Biogen; has taken part in speakers' bureaus for Biogen, As a result, the observed disease progression trajectories to EDSS Genzyme, F. Hoffmann-­L a Roche Ltd., and Merck; and has received ≥7.0 in MSBase may be affected by potential imbalances in some personal grants from Oxford PharmaGenesis and Biogen (prior to 6 | BUTZKUEVEN et al. (a) Placebo (N = 244) 20 OCR 600 mg (N = 488) confirmed disability progression (%) Censored Proportion of patients having 15 HR (95% CI): 0.54 (0.31–0.92); P-value (log rank)=0.022 10 5 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240 Time to onset of confirmed disability progression (Weeks) No. at risk Placebo 244 238 232 225 217 211 204 199 192 185 176 168 159 122 93 72 52 29 11 3 1 OCR 600 mg 487 471 465 459 454 439 432 423 415 407 399 393 384 354 245 212 127 105 31 24 3 (b) Placebo (N = 244) in DBP+ECP 0.8 OCR 600 mg (N = 488) in DBP+ECP Placebo Weibull analysis OCR 600 mg Weibull analysis Proportion of patients with 0.6 EDSS≥7.0 for 24 weeks median 0.4 Distribution AIC‡ Delay, years (95% Cl) Base case Weibull 501.5 7.1 (-4.3 to 18.4) Sensitivity analyses 0.2 Exponential 503.7 14.9 (0.6 to 29.1) Log normal 502.3 17.9 (-16.7 to 52.5) Log logistic 501.7 8.9 (-6.4 to 24.2) Rayleigh 511.9 3.0 (0.5 to 5.4) 0.0 0 5 10 15 20 25 Time (Year) F I G U R E 2 (a) Time to 24-­week confirmed EDSS ≥7.0 during the DBP+ECP.† (b) Time to 24-­week confirmed EDSS ≥7.0 extrapolation. Hazard ratios were estimated by Cox regression, stratified by geographical region (United States vs. ROW) and age (≤45 vs. >45 years). Patients with missing baseline EDSS (n = 1) were excluded from the analysis. Patients with a post-­baseline EDSS ≥7.0 that is sustained for at least 24 weeks are considered as having an event. Patients with EDSS ≥7.0 at the time of treatment discontinuation with no further EDSS score are imputed as having an event. Parameters of the Weibull distribution were estimated based on the observed ORATORIO-­DBP+ECP data, and these parameters applied to the extrapolated curve to enable estimation of the survival function beyond the observation period. † Data cutoff for DBP+ECP in ORATORIO: February 2017. ‡The preferred model is the one with the minimum AIC value. AIC, Akaike information criterion; CI, confidence interval; DBP, double-­b lind period; ECP, extended controlled period; EDSS, Expanded Disability Status Scale; HR, hazard ratio; OCR, ocrelizumab; ROW, rest of world RISK OF REQUIRING A WHEELCHAIR IN PPMS | 7 MSBase PPMS† natural history cohort (N = 775) OCR 600 mg (N = 488) in DBP+ECP+OLE‡ Placebo Weibull analysis§ 0.8 OCR 600 mg Weibull analysis§ Proportion of patients with EDSS ≥7.0 for 24 weeks 0.6 median 0.4 0.2 0.0 0 5 10 15 20 25 Time (Year) No. at risk ORATORIO 244 140 N/A N/A N/A N/A PBO/OCR ORATORIO 487 327 N/A N/A N/A N/A OCR/OCR MSBase 775 443 137 39 10 4 F I G U R E 3 Time to 24-­week confirmed EDSS ≥7.0 in MSBase† and the ORATORIO DBP+ECP+OLE,‡ superimposed onto extrapolated results. Patients with a post-­baseline EDSS ≥7.0, which is sustained for at least 24 weeks, are considered as having an event. Patients with EDSS ≥7.0 at the time of treatment discontinuation with no further EDSS score are imputed as having an event in ORATORIO but are not imputed in MSBase. †Patients with PPMS with baseline EDSS 3.0–­6.5 (N = 775). ‡Data presented up to 312 weeks; OLE data cutoff from January 2019. In ORATORIO, patients with missing baseline EDSS (n = 1) were excluded from the analysis. §Results extrapolated from the DBP+ECP, data cutoff from February 2017. DBP, double-­blind period; ECP, extended controlled period; EDSS, Expanded Disability Status Scale; N/A, not applicable; OCR, ocrelizumab; OLE, open-­label extension; PBO, placebo; PPMS, primary progressive multiple sclerosis June 30, 2018). T.S. has received compensation for serving on steer- for invited speaker's activities. M.O. does not declare any competing ing committees and advisory boards from Biogen. D.H. received interests. A.L. has received personal compensation for consulting, compensation for travel, speaker honoraria. and consultant fees from serving on a scientific advisory board, speaking or other activi- Biogen, Novartis, Merck, Bayer, Sanofi, Roche, and Teva; as well as ties from Biogen, Merck Serono, Mylan, Novartis, Roche, Sanofi/ support for research activities from Biogen. She was also supported Genzyme, and Teva. Her institutions have received research grants by the Czech Ministry of Education project Progress Q27/LF1. S.H. from Novartis (in the last 4 years). B.T. received funding for travel has received previous travel/conference support and speaking hon- and speaker honoraria from Bayer Schering Pharma, CSL Australia, oraria from Biogen, Sanofi-­Genzyme, Merck, Novartis, and Roche. Biogen, and Novartis; and has served on advisory boards for C.S. has received honoraria/research support from Biogen, Merck Biogen, Novartis, Roche, and CSL Australia. G.G. received personal Serono, Novartis, Roche, Almirall, Amgen, and Teva; and has been compensation in the past for serving as a consultant for AbbVie, supported by the Italian MS Foundation. G.I. has received personal Actelion, Atara Bio, Biogen, Celgene, Sanofi Genzyme, Genentech, fees from Bayer, Biogen-­IDec, Novartis, Sanofi, Merck Serono, GlaxoSmithKline, Merck Serono, Novartis, Roche, and Teva; has re- Roche, Actelion, Celgene, and Teva. E.K.H. has received honoraria/ ceived personal compensation from Elsevier for serving as an editor research support from Biogen, F. Hoffmann-­L a Roche Ltd., Merck on Multiple Sclerosis and Related Disorders; and has received financial Serono, Novartis, Sanofi Genzyme, and Teva; has served on advi- support for research activities from Biogen, Roche, Merck, Merck sory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis, Serono, Novartis, Sanofi Genzyme, and Takeda. L.K.'s institution and Sanofi Genzyme; and has been supported by the Czech Ministry (University Hospital Basel) received in the last 3 years and used ex- of Education project Progress Q27/LF1. F.G. received hono- clusively for research support at the department: steering commit- raria or research funding from Biogen, Genzyme, Novartis, Teva tee, advisory board, and consultancy fees from Actelion, Alkermes, Neurosciences, Mitsubishi, and ONO Pharmaceuticals. A.P. does not Almirall, Bayer, Biogen, Celgene/Receptos, df-­mp, Excemed, declare any competing interests. M.G. received consulting fees from GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Teva Canada Innovation, Biogen, Novartis, and Genzyme Sanofi; lec- Pharma, Novartis, F. Hoffmann-­L a Roche Ltd., Sanofi-­Aventis, ture payments from Teva Canada Innovation, Novartis, and EMD; Santhera, Teva, and Vianex; and license fees for Neurostatus-­ and has also received a research grant from Canadian Institutes of UHB products; the Research of the MS Center in Basel has been Health Research. R.H. received research grants from Merck, Biogen, supported by grants from Bayer, Biogen, Novartis, the Swiss MS and Sanofi; and received honoraria from Merck, Roche, and Sanofi Society, the Swiss National Research Foundation, Innoswiss, the 8 | BUTZKUEVEN et al. European Union, and Roche Research Foundations. S.L.H. serves & editing (equal). Alexandre Prat: Conceptualization (supporting); on the board of trustees for Neurona and on scientific advisory investigation (equal); methodology (supporting); validation (equal); boards for Alector, Annexon, Bionure, and Molecular Stethoscope; writing–­review & editing (equal). Marc Girard: Conceptualization and has received travel reimbursement and writing assistance from (supporting); investigation (equal); methodology (supporting); valida- F. Hoffmann-­L a Roche Ltd. and Novartis for CD20-­related meet- tion (equal); writing–­review & editing (equal). Raymond Hupperts: ings and presentations. X.M. has received speaking honoraria and Conceptualization (supporting); investigation (equal); methodol- travel expenses for participation in scientific meetings, has been a ogy (supporting); validation (equal); writing–­review & editing (equal). steering committee member of clinical trials or participated in advi- Marco Onofrj: Conceptualization (supporting); investigation (equal); sory boards of clinical trials in the past years with Actelion, Alexion, methodology (supporting); validation (equal); writing–­review & editing Bayer, Biogen, Celgene, EMD Serono, Genzyme, Immunic, Medday, (equal). Alessandra Lugaresi: Conceptualization (supporting); investi- Merck, Mylan, Nervgen, Novartis, Roche, Sanofi-­Genzyme, Teva gation (equal); methodology (supporting); validation (equal); writing–­ Pharmaceutical, TG Therapeutics, Excemed, MSIF, and NMSS. L.C. review & editing (equal). Bruce Taylor: Conceptualization (supporting); is an employee of F. Hoffmann-­L a Roche Ltd. R.F. is an employee of investigation (equal); methodology (supporting); validation (equal); F. Hoffmann-­L a Roche Ltd. F.M. is an employee and shareholder of writing–­review & editing (equal). Gavin Giovannoni: Conceptualization F. Hoffmann-­L a Roche Ltd. J.O. is currently an employee and share- (supporting); investigation (equal); methodology (supporting); vali- holder of F. Hoffmann-­L a Roche Ltd. During his previous employ- dation (equal); writing–­review & editing (equal). Ludwig Kappos: ment he received personal compensation for consulting, serving on Conceptualization (supporting); investigation (equal); methodol- a scientific advisory board, speaking, or other activities with Teva, ogy (supporting); validation (equal); writing–­review & editing (equal). Biogen, Celgene, EMD Serono, MedDay, Novartis, Roche, Sanofi Stephen L. Hauser: Conceptualization (supporting); investigation Genzyme, WebMD Global, and Allergan. His research and depart- (equal); methodology (supporting); validation (equal); writing–­review ment were supported by grants from Sanofi Genzyme, Biogen, & editing (equal). Xavier Montalban: Conceptualization (supporting); Novartis, and Roche. E.M.-­L .R. is an employee and shareholder of investigation (equal); methodology (supporting); validation (equal); F. Hoffmann-­L a Roche Ltd. A.S. is an employee and shareholder of writing–­review & editing (equal). Licinio Craveiro: Conceptualization F. Hoffmann-­L a Roche Ltd. Q.W. is an employee of F. Hoffmann-­L a (supporting); methodology (equal); validation (equal); writing–­ Roche Ltd. D.W. is an employee of Novartis and shareholder of original draft (equal); writing–­review & editing (equal). Rita Freitas: F. Hoffmann-­L a Roche Ltd. and Novartis. J.S.W. has received per- Conceptualization (lead); methodology (lead); validation (equal); sonal compensation for consulting, serving on a scientific advisory writing–­review & editing (equal). Fabian Model: Conceptualization board, speaking, or other activities with Acorda Therapeutics, (lead); formal analysis (equal); methodology (lead); validation (lead); Alkermes, Brainstorm Cell Therapeutics, EMD Serono, GeNeuro, writing–­original draft (lead); writing–­review & editing (lead). James GW Pharma Ltd., MedDay Pharmaceuticals, NervGen Pharma Corp, Overell: Conceptualization (supporting); methodology (equal); vali- Novartis, Roche/Genentech, and Sanofi Genzyme; royalties are re- dation (equal); writing–­original draft (equal); writing–­review & edit- ceived for out-­licensed monoclonal antibodies through UTHealth ing (equal). Erwan Muros-­Le Rouzic: Conceptualization (supporting); from Millipore Corporation. methodology (equal); validation (equal); writing–­original draft (lead); writing–­review & editing (lead). Annette Sauter: Conceptualization AU T H O R C O N T R I B U T I O N S (equal); formal analysis (equal); methodology (equal); validation (equal); Helmut Butzkueven: Conceptualization (lead); investigation (equal); writing–­original draft (equal); writing–­review & editing (equal). Qing methodology (lead); validation (lead); writing–­original draft (equal); Wang: Conceptualization (equal); formal analysis (lead); methodology writing–­review & editing (equal). Tim Spelman: Conceptualization (lead); validation (lead); writing–­original draft (lead); writing–­review & (equal); formal analysis (lead); methodology (equal); validation (equal); editing (lead). David Wormser: Conceptualization (lead); methodol- writing–­original draft (equal); writing–­review & editing (equal). Dana ogy (lead); validation (equal); writing–­review & editing (equal). Jerry Horakova: Conceptualization (supporting); investigation (equal); S. Wolinsky: Conceptualization (lead); investigation (equal); methodol- methodology (supporting); validation (equal); writing–­review & editing ogy (equal); validation (equal); writing–­review & editing (equal). (equal). Stella Hughes: Conceptualization (supporting); investigation (equal); methodology (supporting); validation (equal); writing–­review & S TAT I S T I C A L A N A LYS I S editing (equal). Claudio Solaro: Conceptualization (supporting); inves- ORATORIO statistical analyses were conducted by Qing Wang (F. tigation (equal); methodology (supporting); validation (equal); writing–­ Hoffmann-­L a Roche Ltd., Basel, Switzerland); MSBase statistical review & editing (equal). Guillermo Izquierdo: Conceptualization analyses were conducted by Tim Spelman (Department of Medicine (supporting); investigation (equal); methodology (supporting); valida- and Melbourne Brain Centre, The Royal Melbourne Hospital, tion (equal); writing–­review & editing (equal). Eva Kubala Havrdova: University of Melbourne, Melbourne, Australia). Conceptualization (supporting); investigation (equal); methodology (supporting); validation (equal); writing–­review & editing (equal). DATA AVA I L A B I L I T Y S TAT E M E N T Francois Grand'Maison: Conceptualization (supporting); investigation For ORATORIO, qualified researchers can request access to indi- (equal); methodology (supporting); validation (equal); writing–­review vidual patient-­level data through the clinical study data request RISK OF REQUIRING A WHEELCHAIR IN PPMS | 9 7. Genentech. Ocrevus (Ocrelizumab) [Full Prescribing Information]. platform (https://vivli.org/). Further details on Roche's criteria https://www.gene.com/downl​o ad/pdf/ocrev​u s_presc​r ibing.pdf. for eligible studies are available here: https://vivli.org/membe​rs/ Accessed January 20, 2020. ourme​mbers/. For further details on Roche's Global Policy on the 8. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. Sharing of Clinical Information and how to request access to related 2017;376(3):209-­220. clinical study documents, see here: https://www.roche.com/resea​ 9. Butzkueven H, Chapman J, Cristiano E, et al. MSBase: an interna- rch_and_devel​opmen​t /who_we_are_how_we_work/clini​c al_trial​s/ tional, online registry and platform for collaborative outcomes our_commi​tment_to_data_shari​ng.htm. For MSBase, data are avail- research in multiple sclerosis. Mult Scler. 2006;12(6):769-­7 74. able from individual investigators upon request to the correspond- 10. Wolinsky JS, Arnold DL, Brochet B, et al. Long-­term follow-­up from the ORATORIO trial of ocrelizumab for primary progressive multi- ing author. ple sclerosis: a post-­hoc analysis from the ongoing open-­label ex- tension of the randomised, placebo-­controlled, phase 3 trial. Lancet ORCID Neurol. 2020;19:998-­1009. Helmut Butzkueven https://orcid.org/0000-0003-3940-8727 11. Polman CH, Reingold SC, Edan G, et al. 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