ORATORIO

Ocrelizumab

ORATORIO showed that ocrelizumab delayed disability progression in primary progressive multiple sclerosis.

Phase
Phase III
Population
Primary progressive multiple sclerosis (PPMS)
Controlled period
Mar 2, 2011 — Jul 23, 2015

What was compared

Randomized 2:1Double-blindPlacebo-controlledEvent-driven
Intervention

Ocrelizumab

600 mg intravenously every 24 weeks

n=488
Comparator

Placebo

Matching intravenous infusions every 24 weeks

n=244
732 randomizedAt least 120 weeks controlled phase

Primary endpoint

Prespecified outcome

12-week confirmed disability progression

Event-driven follow-up

Outcome figure

Primary endpoint results

Intervention Comparator or reference

12-week confirmed disability progression

Participants with progression (%)

Event-driven follow-up
Ocrelizumab
32.9%
Placebo
39.3%

HR 0.76 (95% CI 0.59–0.98; P=0.03).

Selected secondary outcomes

24-week confirmed disability progression

29.6% versus 35.7%; HR 0.75 (P=0.04).

Timed 25-foot walk and MRI

Walking deterioration and MRI lesion/brain-volume outcomes favored ocrelizumab.

Who was studied

Key inclusion criteria

  • Age 18–55 years
  • PPMS diagnosis based on McDonald criteria 2005
  • Baseline EDSS 3.0–6.5
  • Baseline Pyramidal Functional System Score ≥2
  • MS symptom duration <15 years if screening EDSS >5.0, or <10 years if screening EDSS ≤5.0
  • CSF evidence, documented previously or present at screening: elevated IgG index or ≥1 IgG oligoclonal band

Key exclusion criteria

  • History of RRMS, SPMS, or progressive-relapsing MS
  • Contraindication to MRI
  • Contraindication to glucocorticoids or unacceptable glucocorticoid adverse effects
  • Previous B-cell-targeted treatment or other protocol-defined immunosuppressive treatment

Participants at baseline

CharacteristicOcrelizumabN=488PlaceboN=244
Age, years — mean ± SD44.7 ± 7.944.4 ± 8.3
Female sex — n (%)237 (48.6%)124 (50.8%)
Time since MS symptom onset, years — mean ± SD6.7 ± 4.06.1 ± 3.6
Time since PPMS diagnosis, years — mean ± SD2.9 ± 3.22.8 ± 3.3
EDSS — mean ± SD4.7 ± 1.24.7 ± 1.2
No DMT use in the previous 2 years — n (%)433 (88.7%)214 (87.7%)
Gadolinium-enhancing T1 lesions present — n/N (%)133/484 (27.5%)60/243 (24.7%)

SD: standard deviation; EDSS: Expanded Disability Status Scale; DMT: disease-modifying therapy.

Source: Montalban et al., NEJM 2017, Table 1

Safety signal

  • Infusion-related reactions occurred in 39.9% with ocrelizumab versus 25.5% with placebo; 2 ocrelizumab-treated participants (0.4%) withdrew because of these reactions.
  • Upper-respiratory infections and oral herpes were more frequent with ocrelizumab.
  • Neoplasms occurred in 2.3% with ocrelizumab and 0.8% with placebo.

Why it mattered

ORATORIO supplied pivotal evidence for an approved disease-modifying therapy in PPMS, a population previously lacking an established treatment option. The benefit was demonstrated in participants meeting specific age, disability, disease-duration, and CSF criteria, which matters when applying the result.

Important limitation

Age, disability, and disease-duration criteria selected a narrower and generally earlier PPMS population than many patients seen in practice.

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