Trial Oversight

The sponsor, F. Hoffmann–La Roche, designed the trial in consultation with members of the ORATORIO trial steering committee. Data were collected by the investigators and analyzed by the sponsor; the results were reviewed by the sponsor and steering committee. An independent data and safety monitoring committee reviewed safety data on an ongoing basis and provided guidance on trial continuation, modification, or termination. (See the trial oversight section in the Supplementary Appendix, available with the full text of this article at NEJM.org.) All authors participated in the writing of the manuscript and approved the draft that was submitted for publication. The first draft of the manuscript was written by the first and last authors, with medical writing assistance funded by the sponsor. The authors vouch for the accuracy and completeness of the data and data analyses and for the fidelity of the trial to the protocol (available at NEJM.org). The trial was conducted in accordance with the provisions of the International Conference on Harmonisation Guidelines for Good Clinical Practice18 and the Declaration of Helsinki.19

Patients

Key eligibility criteria were an age of 18 to 55 years, a diagnosis of primary progressive multiple sclerosis (according to the 2005 revised McDonald criteria),20 a score on the Expanded Disability Status Scale (EDSS) of 3.0 to 6.5 at screening (range, 0 to 10.0, with higher scores indicating greater disability),21 a score on the pyramidal functions component of the Functional Systems Scale of at least 2 (range, 0 to 6, with higher scores indicating greater disability), a duration of multiple sclerosis symptoms of less than 15 years in patients with an EDSS score of more than 5.0 at screening or less than 10 years in patients with an EDSS score of 5.0 or less at screening, and a documented history or the presence at screening of an elevated IgG index or at least one IgG oligoclonal band detected in the cerebrospinal fluid. Key exclusion criteria were a history of relapsing–remitting, secondary progressive, or progressive relapsing multiple sclerosis; contraindications to magnetic resonance imaging (MRI); contraindications to or unacceptable side effects from oral or intravenous glucocorticoids; and previous treatment with B-cell–targeted therapies and other immunosuppressive medications, as defined in the protocol.

Trial Design

Patients were randomly assigned in a 2:1 ratio to receive 600 mg of ocrelizumab by intravenous infusion (administered as two 300-mg infusions 14 days apart) or matching placebo every 24 weeks (Fig. S1 in the Supplementary Appendix). The trial was event-driven, such that double-blind treatment was administered for a minimum of five doses (120 weeks) until the occurrence in the trial cohort of approximately 253 events of disability progression that was confirmed for at least 12 weeks. Early enrollees in the trial received more than five double-blind doses, dependent on the time of enrollment and the number of confirmed disability progression events that had occurred (Table S1 in the Supplementary Appendix). All patients received intravenous methylprednisolone (100 mg) before infusion. Optional prophylaxis with analgesics or antipyretics and antihistamine was recommended before infusion, and adjustment of the infusion rate and symptomatic treatment during infusion were permitted to manage infusion-related reactions.

Randomization that was stratified according to geographic region and age was performed centrally by an independent interactive Web-response system. Each trial center had separate treating and examining investigators. An independent, trained investigator who was unaware of the trial-group assignments and was certified in administering the EDSS conducted the neurologic examination and scored the EDSS. EDSS assessment and data collection were captured with the use of a real-time, electronic tablet data-entry system. Multiple Sclerosis Functional Composite analysis was performed by the examining investigator or a qualified designee who was unaware of the trial-group assignments. MRI scans were analyzed independently at a central MRI reading center by staff members who were unaware of the trial-group assignments. (See the section on additional methodologic details in the Supplementary Appendix.)

Patients who completed the blinded treatment phase were eligible to enter the open-label extension phase of the trial, after the database lock and unblinding of trial results. Patients who discontinued prematurely or who did not wish to enter the open-label extension phase were included in the safety follow-up.

Trial End Points

The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis, in which disability progression was defined as an increase in the EDSS of at least 1.0 point from baseline that was sustained on subsequent visits for at least 12 weeks if the baseline score was 5.5 or less or an increase of at least 0.5 points that was sustained for at least 12 weeks if the baseline score was more than 5.5. If the primary end point reached a significance level of P<0.05, secondary end points were tested in the following hierarchical order as long as each preceding end point reached a significance level of P<0.05: the percentage of patients with disability progression confirmed at 24 weeks in a time-to-event analysis, change in performance on the timed 25-foot walk from baseline to week 120, change in the total volume of brain lesions on T 2 -weighted MRI from baseline to week 120, change in brain volume from week 24 to week 120, and change in the Physical Component Summary score of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), version 2, from baseline to week 120 (range, 0 to 100, with higher scores indicating better physical-health–related quality of life. Drug safety and adverse events were also analyzed. There were 16 exploratory end points, including the time to onset of 12-week and 24-week confirmed composite disability progression (defined as the first confirmed occurrence of an increase in the EDSS score, an increase in the time to perform the timed 25-foot walk of ≥20%, or an increase in the time to complete the 9-hole peg test of ≥20%), time to a sustained increase of at least 20% in performance on the timed 25-foot walk, time to a sustained increase of at least 20% in the 9-hole peg test, total number of new or enlarging lesions on T 2 -weighted images from baseline to week 120, and pharmacokinetics, immunogenicity, and pharmacodynamics of ocrelizumab.

Statistical Analysis

All efficacy end points were analyzed in the intention-to-treat population (all randomly assigned patients). The time to confirmed disability progression was analyzed with the use of a two-sided log-rank test for differences between the ocrelizumab and placebo groups that was stratified according to region (United States vs. rest of the world) and age (≤45 vs. >45 years) at baseline; a P value of less than 0.05 was considered to indicate statistical significance. Cox regression was used for estimation of hazard ratios. The sample size was based on an estimated rate of 12-week confirmed disability progression of 0.30 for the ocrelizumab group and 0.43 for the placebo group over a period of 2 years (hazard ratio, 0.64). With a 2:1 ratio for randomization between the ocrelizumab and placebo groups, using a two-sided log-rank test, we calculated that a total sample of 630 patients would provide 80% statistical power to maintain a type I error rate of 0.01, assuming a dropout rate of approximately 20%. For the primary and first secondary efficacy end points (i.e., confirmed disability progression that was sustained for ≥12 weeks and ≥24 weeks, respectively), patients with missing data on the EDSS score at baseline were excluded from the analysis, and patients with an initial disability progression during the blinded treatment period who discontinued ocrelizumab or placebo early and did not have a subsequent visit with confirmatory measurement of the EDSS score were considered to have confirmed disability progression (Table S2 in the Supplementary Appendix). Hierarchical testing of each secondary efficacy end point was performed. (For details, see the Statistical Analysis section in the Supplementary Appendix.)