Ocrelizumab Phase 2
(2011)Objective
Ocrelizumab - To assess the efficacy and safety of two doses of the B-cell depleting therapy ocrelizumab versus placebo and interferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS).
Study Summary
• Ocrelizumab also significantly reduced the annualized relapse rate compared to placebo.
Intervention
Patients with RRMS were randomized to one of four groups for a 24-week period: intravenous placebo, intravenous ocrelizumab 600 mg, intravenous ocrelizumab 2000 mg, or intramuscular interferon beta-1a.
Inclusion Criteria
Adults 18–55 years with RRMS, EDSS 1.0–6.0, 1–3 relapses in prior 2 years, at least one Gd-enhancing lesion at screening.
Study Design
Arms: OCR 600 mg; OCR 2000 mg; Placebo; Interferon beta-1a
Patients per Arm: OCR 600 mg: 82; OCR 2000 mg: 81; Placebo: 54; IFN: 54; Total: 220
Outcome
• The annualized relapse rate was 0.13 for the 600 mg ocrelizumab group and 0.17 for the 2000 mg group, compared to 0.64 for the placebo group.
Bottom Line
In this phase 2 trial, both low-dose (600 mg) and high-dose (2000 mg) ocrelizumab resulted in a profound and rapid reduction in inflammatory disease activity, as measured by gadolinium-enhancing MRI lesions and clinical relapses, over 24 weeks compared to placebo. The treatment was generally well tolerated, supporting a role for B-cell targeted therapy in multiple sclerosis.
Major Points
- This was a multicentre, randomised, double-blind, placebo-controlled phase 2 trial that also included an open-label, rater-masked interferon beta-1a arm.
- 220 patients with relapsing-remitting multiple sclerosis were randomized 1:1:1:1 to receive placebo, ocrelizumab 600 mg, ocrelizumab 2000 mg, or interferon beta-1a.
- The primary endpoint was the total number of gadolinium-enhancing lesions (GEL) on T1-weighted MRI at weeks 12, 16, 20, and 24.
- Compared to placebo, the number of GEL at week 24 was reduced by 89% in the 600 mg ocrelizumab group and by 96% in the 2000 mg ocrelizumab group (both P<0.0001).
- Annualised relapse rates over 24 weeks were significantly lower in the ocrelizumab groups compared to placebo (0.13 for 600 mg and 0.17 for 2000 mg vs 0.64 for placebo).
- Serious adverse events were infrequent and occurred at similar rates across the ocrelizumab and placebo groups.
Study Design
- Study Type
- Phase 2, multicentre, randomised, parallel, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind for ocrelizumab and placebo groups; rater-masked for the open-label interferon beta-1a group.
- Sample Size
- 220
- Follow-up
- 96 weeks (primary analysis at 24 weeks)
- Centers
- 79
- Countries
- 20 countries
Primary Outcome
Definition: Total number of gadolinium-enhancing T1 lesions on brain MRI scans over weeks 12, 16, 20, and 24.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Mean 5.5 lesions (Placebo) | Mean 0.6 lesions (600 mg Ocrelizumab); Mean 0.2 lesions (2000 mg Ocrelizumab) | - | <0.0001 (for both ocrelizumab doses vs placebo) |
Limitations & Criticisms
- The open-label, rater-masked design of the interferon beta-1a arm makes comparisons with this group exploratory.
- The trial was a phase 2 study with a relatively small sample size, designed primarily to assess MRI outcomes and safety, not powered for definitive clinical efficacy.
- The duration of the placebo-controlled period was short (24 weeks), limiting assessment of long-term efficacy and safety.
- One death occurred in the 2000 mg ocrelizumab group, for which a contribution from the study drug could not be excluded.
Citation
Lancet. 2011;378(9805):1779-1787.