HERCULES (multiple sclerosis)
Trial question
What is the role of tolebrutinib in patients with nonrelapsing secondary progressive multiple sclerosis?
Study design
Multi-center
Double blinded
RCT
Population
Characteristics of study participants
62.0% female
38.0% male
N = 1131
1131 patients (696 female, 435 male).
Inclusion criteria: adult patients, aged 18-60 years, with nonrelapsing secondary progressive multiple sclerosis.
Key exclusion criteria: short life expectancy; history of organ transplant; HIV; transplantation; progressive multifocal leukoencephalopathy, active hepatitis B or C; active or latent tuberculosis; persistent chronic or active or recurring system infections; history of malignancy within 5 years prior to screening; history of alcohol or drug abuse within 1 year prior to screening; hospitalization for psychiatric disease within 2 years prior to screening.
Interventions
N=754 tolebrutinib (at a dose of 60 mg once daily).
N=377 placebo (matching placebo).
Primary outcome
Rate of confirmed disability progression sustained for at least 6 months
22.6%
30.7%
30.7 %
23.0 %
15.3 %
7.7 %
0.0 %
Tolebrutinib
Placebo
Significant
decrease ▼
NNT = 12
Significant decrease in the rate of confirmed disability progression sustained for at least 6 months (22.6% vs. 30.7%; HR 0.69, 95% CI 0.55 to 0.88).
Secondary outcomes
Significant decrease in the rate of confirmed disability progression sustained for ≥ 3 months (27.6% vs. 34.2%; HR 0.76, 95% CI 0.61 to 0.94).
Significant decrease in mean annualized rate of new or enlarging lesions on T2-weighted MRI (1.84 lesions vs. 2.95 lesions; RR 0.62, 95% CI 0.43 to 0.9).
No significant difference in the percentage of patients achieving 20% improvement in the score on the Nine-Hole Peg Test sustained for ≥ 3 months (19% vs. 19.6%; HR 0.97, 95% CI 0.74 to 1.29).
Safety outcomes
No significant difference in adverse event.
Conclusion
In adult patients, aged 18-60 years, with nonrelapsing secondary progressive multiple sclerosis, tolebrutinib was superior to placebo with respect to the rate of confirmed disability progression sustained for at least 6 months.
Reference
Robert J Fox, Amit Bar-Or, Anthony Traboulsee et al. Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis. N Engl J Med. 2025 Apr 8. Online ahead of print.
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