DEFINE

Dimethyl fumarate

DEFINE demonstrated that oral dimethyl fumarate reduced the probability of relapse, disability progression, and MRI lesion activity versus placebo.

Phase: Phase III
Population: Relapsing-remitting multiple sclerosis (RRMS)
Controlled period: Jan 2007 — Feb 2011

What was compared

RandomizedDouble-blindPlacebo-controlledMulticenter

Intervention

Dimethyl fumarate 240 mg twice daily

Orally twice daily

Comparator

Placebo

Matching oral capsules

Additional randomized arm

Dimethyl fumarate 240 mg three times daily

Orally three times daily

1,234 randomized96 weeks controlled phase

Primary endpoint

Prespecified outcome

Participants with a relapse

2 years

Outcome figure

Primary endpoint results

Intervention Comparator or reference

Participants with a relapse

Participants with relapse (%)

2 years

Dimethyl fumarate twice daily

27%

Dimethyl fumarate three times daily

26%

Placebo

46%

Both regimens reduced relapse risk by about half (P<0.001).

Selected secondary outcomes

Annualized relapse rate

0.17 and 0.19 with dimethyl fumarate versus 0.36 with placebo.

Disability and MRI

Confirmed disability progression and MRI activity both favored treatment.

Study population

Randomized: 1,234 randomized
Age: Mean 38.5 years; eligible 18–55
Sex: 908 women (74%)
Disability: EDSS 0–5.0
Disease definition: Relapsing-remitting multiple sclerosis

Who entered the trial

Key inclusion criteria

Defined based on McDonald criteria 2005
Relapsing-remitting clinical course
Baseline EDSS 0–5.0

Key exclusion criteria

Other chronic immune disease or malignancy
Clinically important urologic, pulmonary, or gastrointestinal disease
Pregnancy or breastfeeding

Safety signal

Flushing and gastrointestinal events were most frequent early in treatment.
Lymphocyte counts decreased and liver aminotransferase levels increased with dimethyl fumarate.

Why it mattered

DEFINE was one of the two pivotal trials establishing an oral fumarate regimen as an effective option for relapsing-remitting MS.

Important limitation

The placebo comparison did not answer relative efficacy against established disease-modifying therapies, and the controlled period was too short for rare delayed harms.