CONFIRM

Dimethyl fumarate

CONFIRM showed that oral dimethyl fumarate reduced relapses and MRI activity versus placebo while including glatiramer acetate as an active reference.

Phase
Phase III
Population
Relapsing-remitting multiple sclerosis (RRMS)
Controlled period
Jun 2007 — Aug 2011

What was compared

RandomizedDouble-blindPlacebo-controlledActive reference
Intervention

Dimethyl fumarate 240 mg twice daily

Orally twice daily

n=359
Comparator

Placebo

Matching oral capsules

n=363

Additional randomized arms

Dimethyl fumarate 240 mg three times daily

Orally three times dailyn=345

Glatiramer acetate

20 mg subcutaneously once daily; active referencen=350
1,417 randomized96 weeks controlled phase

Primary endpoint

Prespecified outcome

Annualized relapse rate

2 years

Outcome figure

Primary endpoint results

Intervention Comparator or reference

Annualized relapse rate

Relapses per participant-year

2 years
Dimethyl fumarate twice daily
0.22
Dimethyl fumarate three times daily
0.20
Glatiramer acetate
0.29
Placebo
0.40

44% and 51% lower with dimethyl fumarate; 29% lower with glatiramer acetate.

Selected secondary outcomes

Disability progression

Reductions versus placebo were not statistically significant.

MRI lesions

Both dimethyl fumarate regimens and glatiramer acetate improved key MRI outcomes.

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
  • Previous glatiramer acetate or recent treatment with protocol-prohibited medications

Participants at baseline

CharacteristicDimethyl fumarate twice dailyN=359Dimethyl fumarate three times dailyN=345Glatiramer acetateN=350PlaceboN=363
Age, years — mean ± SD37.8 ± 9.437.8 ± 9.436.7 ± 9.136.9 ± 9.2
Female sex — n (%)245 (68%)250 (72%)247 (71%)251 (69%)
Time since MS diagnosis, years — mean ± SD4.9 ± 5.14.6 ± 5.24.4 ± 4.74.8 ± 5.0
EDSS — mean ± SD2.6 ± 1.22.5 ± 1.22.6 ± 1.22.6 ± 1.2
Relapses in previous 12 months — mean ± SD1.3 ± 0.61.4 ± 0.71.4 ± 0.61.4 ± 0.8
Previous approved DMT — n (%)101 (28%)100 (29%)103 (29%)111 (31%)

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

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

Safety signal

  • Flushing and gastrointestinal events were more frequent with dimethyl fumarate.
  • Upper respiratory tract infection occurred in 10% with twice-daily dimethyl fumarate and 14% with three-times-daily dosing, versus 9% with placebo.
  • Lymphocyte counts decreased with dimethyl fumarate; injection-related events were more frequent with glatiramer acetate.

Why it mattered

CONFIRM replicated dimethyl fumarate’s relapse and MRI efficacy in a second large trial and included glatiramer acetate as an active reference. Disability progression was not significantly reduced, and the study was not designed to establish superiority over glatiramer acetate.

Important limitation

The study was not designed or powered to establish superiority or noninferiority between dimethyl fumarate and glatiramer acetate.

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