HERCULES was a unique trial design in nrSPMS, a population progressing independent of relapses ^1,2

HERCULES inclusion criteria:

• The HERCULES trial was a phase 3, multicenter, randomized (2:1), double-blind, placebo-controlled, event-driven trial, studied during a treatment period of 24-48 months, comparing CENRIFKI vs placebo in patients with nrSPMS^1,2,4✝
• The trial included a diverse range of patients^1,4
• In HERCULES, nrSPMS was defined based on an absence of relapses for at least 2 years, with or without MRI activity at baseline^1,4
• Patients with ALT, AST, total bilirubin greater than 1.5 x ULN (unless due to Gilbert syndrome or non-liver related disorder) or ALP greater than 2 x ULN were excluded¹

HERCULES was a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial comparing CENRIFKI vs placebo in patients with nrSPMS^1,2* 

Primary endpoint

• Confirmed disability progression sustained for ≥6 months (6-month CDP)¹*

Secondary endpoints^4†

• Confirmed disability progression sustained for ≥3 months*
• Annualized rate of new or enlarging lesions on T2-weighted MRI
• 20% increase in the score on the Nine-Hole Peg Test sustained for ≥3 months
• 20% increase in the score on the Timed 25-Foot Walk Test sustained for ≥3 months
• Confirmed disability improvement sustained for 6 months‡
• Percentage change in brain volume from Month 6 to end-of-trial visit

^*Confirmed disability progression was defined as an increase from baseline in the EDSS score of at least 1.0 point if the baseline score was 5.0 or less, or an increase from baseline of at least 0.5 points if the baseline score was greater than 5.0.^1
†The secondary endpoints are ordered hierarchically. The widths of the confidence intervals have not been adjusted for multiplicity and therefore should not be used to infer treatment effects.^4
‡Confirmed lessening of disability (disability improvement) was defined as a decrease in the EDSS score of at least 1.0 point from baseline.⁴

MRl=magnetic resonance imaging; nrSPMS=non-relapsing secondary progressive multiple sclerosis.

*The EDSS is a non-linear scale used to assess MS-related disability, ranging from 0 (normal exam) to 10 (MS-related death).³

^†Disability assessments were conducted 1 month prior to baseline, at baseline, and then every 3 months until the end of the study. MRI scans were conducted at 1 month prior to baseline, at 6 months, and then every 6 months thereafter.^1,4

ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CDP=confirmed disability progression; EDSS=Expanded Disability Status Scale; MRI=magnetic resonance imaging; MS=multiple sclerosis; nrSPMS=non-relapsing secondary progressive multiple sclerosis.

First and only treatment to reduce the risk of 6 month confirmed disability progression in patients with nrSPMS^1,4

HERCULES was an event-driven trial with a variable treatment duration up to 48 months¹

*6-month CDP is defined as an increase of ≥1.0 point from baseline EDSS score when baseline score is <5.0 or an increase of ≥0.5 points when baseline score is >5.0 confirmed over ≥6 months.¹

^{ARR=annualized relapse rate; CDI=confirmed disability improvement; CDP=confirmed disability progression; CI=confidence interval; EDSS=Expanded Disability Status Scale; HR=hazard ratio; 9-HPT=9-Hole Peg Test; nrSPMS=non-relapsing secondary progressive multiple sclerosis; NS=not significant; T25-FW=Timed 25-Foot Walk Test.}

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