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.

Who was studied

Key inclusion criteria

Age 18–55 years
RRMS diagnosis based on McDonald criteria 2005
Baseline EDSS 0–5.0
At least 1 relapse in the previous year, or at least 1 gadolinium-enhancing lesion on MRI within 6 weeks before randomization

Key exclusion criteria

Progressive MS
Clinically significant illness or prespecified laboratory abnormalities
Recent treatment with protocol-prohibited medications

Participants at baseline

Characteristic	Dimethyl fumarate twice dailyN=410	Dimethyl fumarate three times dailyN=416	PlaceboN=408
Age, years — mean ± SD	38.1 ± 9.1	38.8 ± 8.8	38.5 ± 9.1
Female sex — n (%)	296 (72%)	306 (74%)	306 (75%)
Time since MS diagnosis, years — mean ± SD	5.6 ± 5.4	5.1 ± 5.3	5.8 ± 5.8
EDSS — mean ± SD	2.40 ± 1.29	2.36 ± 1.19	2.48 ± 1.24
Relapses in previous 12 months — mean ± SD	1.3 ± 0.7	1.3 ± 0.6	1.3 ± 0.7
Previous approved MS medication — n (%)	162 (40%)	168 (40%)	172 (42%)

SD: standard deviation; EDSS: Expanded Disability Status Scale.

Source: Gold et al., NEJM 2012, Table 1

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 demonstrated relapse, MRI, and confirmed-disability effects for oral dimethyl fumarate in RRMS. Together with CONFIRM it established the fumarate treatment program, while the differing disability results showed why both trials must be considered.

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.