PDF: OPERA I & II
(2016)Objective
Ocrelizumab - To compare the efficacy and safety of ocrelizumab versus interferon beta-1a in patients with relapsing multiple sclerosis.
Study Summary
• Ocrelizumab reduced the annualized relapse rate by 46-47%, disability progression by 40%, and the number of new ilesions by 94-95%.
• The most common side effect of ocrelizumab was infusion-related reactions.
Intervention
Two identical trials randomizing patients with relapsing multiple sclerosis 1:1 to receive either intravenous ocrelizumab (600 mg every 24 weeks) or subcutaneous interferon beta-1a (44 μg three times weekly) for 96 weeks.
Study Design
Arms: Array
Outcome
• In a pooled analysis, ocrelizumab resulted in a 40% lower risk of 12-week confirmed disability progression (HR 0.60, p<0.001).
• Ocrelizumab treatment was associated with a 94-95% reduction in gadolinium-enhancing lesions on MRI compared to interferon beta-1a.
Bottom Line
In two large, identical phase 3 trials, ocrelizumab demonstrated superior efficacy over interferon beta-1a in treating relapsing multiple sclerosis. It significantly reduced the annualized relapse rate, slowed disability progression, and suppressed MRI lesion activity over a 96-week period, with an acceptable safety profile.
Major Points
- Two identical phase 3, randomized, double-blind, double-dummy, active-controlled trials (OPERA I and OPERA II) were conducted, enrolling a total of 1656 patients with relapsing multiple sclerosis.
- Patients were randomized 1:1 to receive either intravenous ocrelizumab (600 mg every 24 weeks) or subcutaneous interferon beta-1a (44 μg three times weekly) for 96 weeks.
- The primary endpoint, the annualized relapse rate, was significantly lower with ocrelizumab than with interferon beta-1a in both trials (Trial 1: 0.16 vs. 0.29, a 46% reduction; Trial 2: 0.16 vs. 0.29, a 47% reduction; P<0.001 for both).
- In a pooled analysis, the risk of 12-week confirmed disability progression was 40% lower with ocrelizumab (9.1% vs. 13.6%; HR 0.60; P<0.001).
- Ocrelizumab dramatically reduced MRI activity, with a 94-95% lower number of gadolinium-enhancing lesions compared to interferon beta-1a (P<0.001).
- Infusion-related reactions were common with ocrelizumab (34.3%), but serious infections were less frequent than with interferon beta-1a (1.3% vs. 2.9%). Neoplasms occurred in 0.5% of ocrelizumab patients and 0.2% of interferon beta-1a patients.
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group trials
- Randomization
- Yes
- Blinding
- Double-blind, double-dummy
- Sample Size
- 1656
- Follow-up
- 96 weeks
- Centers
- 307
Primary Outcome
Definition: Annualized relapse rate at 96 weeks.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0.29 | 0.16 | - (0.40 to 0.72 (for rate ratio in Trial 1); 0.40 to 0.71 (for rate ratio in Trial 2)) | <0.001 |
Limitations & Criticisms
- Longer-term studies are required to fully characterize the safety profile of ocrelizumab, particularly regarding the numerical imbalance in reported neoplasms.
- The trials did not include a placebo arm, but compared ocrelizumab against an established active comparator, which is a strength.
- The effect on certain patient populations (eg, pregnant patients, those with acute coronary syndrome or stroke) was not studied.
Citation
N Engl J Med 2016;376:221-34.