← Back
NeuroTrials.ai
Neurology Clinical Trial Database

ORATORIO

Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis

Share Share Copied! Compare

Year of Publication: 2016

Authors: X. Montalban, S.L. Hauser, L. Kappos, ..., for the ORATORIO Clinical Investigators

Journal: The New England Journal of Medicine

Citation: N Engl J Med 2016;376:209-20.

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1606468

Clinical Question

To determine the efficacy and safety of ocrelizumab, a B-cell depleting humanized monoclonal antibody, compared to placebo in patients with primary progressive multiple sclerosis (PPMS).

Bottom Line

In patients with primary progressive multiple sclerosis, ocrelizumab significantly lowered the rates of clinical disability progression and MRI lesion progression compared to placebo over a median of 2.9 years. While associated with more infusion-related reactions and upper respiratory infections, there was no significant difference in the rates of serious adverse events.

Major Points

  • ORATORIO was a phase 3, randomized, double-blind, placebo-controlled trial in 732 patients with primary progressive multiple sclerosis (PPMS).
  • Patients were randomized 2:1 to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks.
  • The primary endpoint was the percentage of patients with disability progression confirmed at 12 weeks.
  • The primary endpoint was met: 32.9% of patients in the ocrelizumab group had 12-week confirmed disability progression, compared to 39.3% in the placebo group (Hazard Ratio [HR] 0.76; P=0.03).
  • Key secondary endpoints were also met, including a lower rate of 24-week confirmed disability progression, less worsening on the timed 25-foot walk, a decrease in T2 lesion volume (versus an increase with placebo), and less brain volume loss with ocrelizumab.
  • Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab. Neoplasms were reported in 2.3% of ocrelizumab patients versus 0.8% of placebo patients.

Design

Study Type: Phase 3, randomized, parallel-group, double-blind, placebo-controlled trial

Randomization: 1

Blinding: Double-blind (patients and investigators)

Enrollment Period: March 3, 2011, through December 27, 2012

Follow-up Duration: At least 120 weeks (event-driven trial, median duration 2.9 years)

Countries:

Sample Size: 732

Analysis: Intention-to-treat analysis. The time to confirmed disability progression was analyzed using a two-sided log-rank test, stratified by region and age. A hierarchical testing procedure was used for secondary endpoints.

Inclusion Criteria

  • Age 18 to 55 years
  • Diagnosis of primary progressive multiple sclerosis (2005 revised McDonald criteria)
  • Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5
  • Duration of MS symptoms <15 years (if EDSS >5.0) or <10 years (if EDSS ≤5.0)
  • Elevated IgG index or at least one IgG oligoclonal band in cerebrospinal fluid

Exclusion Criteria

  • History of relapsing-remitting, secondary progressive, or progressive relapsing multiple sclerosis
  • Previous treatment with B-cell-targeted therapies or other specified immunosuppressive medications
  • Contraindications to MRI or glucocorticoids

Baseline Characteristics

CharacteristicControlActive
GroupPlacebo (N=244)Ocrelizumab (N=488)
Age - yr, Mean44.4±8.344.7±7.9
Female sex - no. (%)124 (50.8)237 (48.6)
Score on EDSS, Mean4.7±1.24.7±1.2
Gadolinium-enhancing lesions - no./total no. (%)60/243 (24.7)133/484 (27.5)

Arms

FieldControlOcrelizumab
InterventionIntravenous placebo administered as two 300-mg equivalent infusions 14 days apart, every 24 weeks.Intravenous ocrelizumab 600 mg, administered as two 300-mg infusions 14 days apart, every 24 weeks.
DurationAt least 120 weeksAt least 120 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Percentage of patients with disability progression confirmed at 12 weeks, defined as a sustained increase in the Expanded Disability Status Scale (EDSS) score.Primary39.3% (96/244)32.9% (160/487)0.760.03
Percentage of patients with disability progression confirmed at 24 weeksSecondary35.7% (87/244)29.6% (144/487)HR 0.75 (95% CI, 0.58 to 0.98)0.04
Mean percent change in performance on timed 25-foot walk from baseline to week 120Secondary55.1%38.9%0.04
Adjusted geometric mean percent change in total volume of T2 lesions from baseline to week 120Secondary+7.43%-3.37%<0.001
Mean percent change in brain volume from week 24 to 120Secondary-1.09%-0.90%0.02
NeoplasmsAdverse0.8% (2/239)2.3% (11/486)
Infusion-related reactionsAdverse25.5% (61/239)39.9% (194/486)
Serious adverse eventAdverse22.2% (53/239)20.4% (99/486)

Subgroup Analysis

A subgroup analysis of efficacy in patients with and without gadolinium-enhancing lesions at baseline was directionally consistent with the findings in the overall trial population.

Criticisms

  • Extended observation is required to determine the long-term safety and efficacy of ocrelizumab.
  • The imbalance in the number of reported neoplasms between the ocrelizumab and placebo groups warrants ongoing evaluation.

Funding

F. Hoffmann-La Roche

Based on: ORATORIO (The New England Journal of Medicine, 2016)

Authors: X. Montalban, S.L. Hauser, L. Kappos, ..., for the ORATORIO Clinical Investigators

Citation: N Engl J Med 2016;376:209-20.

Content summarized and formatted by NeuroTrials.ai.