HERCULES
What it found
The main measure showed a statistically significant benefit.
| Measure | Estimate | 95% CI | p |
|---|---|---|---|
| Time to Onset of 6-Month Confirmed Disability Progression (CDP) as Assessed by Expanded Disability Status Scale (EDSS) | Hazard Ratio (HR) 0.693 | 0.546–0.880 | 0.0026 |
Statistical analysis as posted on ClinicalTrials.gov.
What was tested
Treatment tested
- Tolebrutinib
Tyrosine-protein kinase BTK inhibitor
Placebo or sham
- Placebo to match Tolebrutinib
Results by group
Time to Onset of 6-Month Confirmed Disability Progression (CDP) as Assessed by Expanded Disability Status Scale (EDSS)
Baseline (Day 1) up to approximately 47 months
| Group | Value | Interval | Number analysed |
|---|---|---|---|
| DB: Placebo | 11.97 months | 0.5–39.1 | 377 |
| DB: Tolebrutinib 60 mg | 12.04 months | 2.8–37.4 | 754 |
DB: Placebo
DB: Tolebrutinib 60 mg
p = 0.0026; Hazard Ratio (HR) 0.693 (95% CI 0.546–0.880)
Values as posted on ClinicalTrials.gov. Outcomes measured differently across trials are not directly comparable.
Safety
| Group | Participants at risk | Serious adverse events | Deaths |
|---|---|---|---|
| DB: Placebo | 375 | 39 (10.4%) | 1 |
| DB: Tolebrutinib 60 mg | 752 | 113 (15.0%) | 2 |
| OL: Placebo/Tolebrutinib 60 mg | 76 | 9 (11.8%) | 0 |
| OL: Tolebrutinib 60 mg/Tolebrutinib 60 mg | 120 | 11 (9.2%) | 0 |
As posted on ClinicalTrials.gov. Serious adverse events include any serious health event during the trial, whether or not the treatment caused it.
What it measured
Main measures
Time to Onset of 6-Month Confirmed Disability Progression (CDP) as Assessed by Expanded Disability Status Scale (EDSS)
Baseline (Day 1) up to approximately 47 months
Disability progressionBladder, bowel and sexual function6-month confirmed disability progression (CDP) ; Time to onset of 6 months CDP defined as follows:
Disability progression
Other measures (17)
Time to Onset of 3-month Confirmed Disability Progression as Assessed by Expanded Disability Status Scale
Baseline (Day 1) up to approximately 47 months
Disability progressionBladder, bowel and sexual functionMean Number of New and/or Enlarging T2-hyperintense Lesions Per Year
Baseline (Day 1) up to approximately 47 months
MRI lesionsTime to Onset of Sustained 20% Increase in the 9-hole Peg Test (HPT) for at Least 3 Months
Baseline (Day 1) up to approximately 47 months
Disability progressionArm and hand functionTime to Onset of Sustained 20% Increase in the Timed 25-foot Walk (T25-FW) for at Least 3 Months
Baseline (Day 1) up to approximately 47 months
Disability progressionWalking and mobilityTime to Onset of 6-month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale
Baseline (Day 1) up to approximately 47 months
Disability progressionBladder, bowel and sexual functionPercent Change in Brain Volume at EOS Compared to Month 6
Month 6 to EOS (up to approximately 47 months)
MRI lesionsBrain volume lossChange From Baseline in Cognitive Function as Assessed by Symbol Digit Modalities Test (SDMT) at EOS
Baseline (Day 1) to EOS (up to approximately 47 months)
Thinking and memoryChange From Baseline in Cognitive Function as Assessed by California Verbal Learning Test Second Edition (CVLT-II) at EOS
Baseline (Day 1) to EOS (up to approximately 47 months)
Thinking and memoryChange From Baseline in Multiple Sclerosis Quality of Life-54 (MSQoL-54) Questionnaire Score at EOS
Baseline (Day 1) to EOS (up to approximately 47 months)
Thinking and memoryBladder, bowel and sexual functionPainQuality of life (reported by participants)Number of Participants With Treatment-emergent Adverse Events (AEs), Treatment-emergent Serious AEs, Treatment-emergent AEs Leading to Permanent Study Intervention Discontinuation, and Treatment-emergent Adverse Events of Special Interest (AESIs)
From first dose of study intervention (Day 1) up to end of follow-up, up to approximately 47 months
Safety
Who could take part
Progressive MS · 18 to 60
Inclusion criteria : * 18 to 60 years of age inclusive * Diagnosis of nonrelapsing secondary progressive multiple sclerosis according to the 2017 McDonald criteria * Expanded disability status scale (EDSS) between 3.0 to 6.5 points inclusive, at screening * The participant must have documented evidence of disability progression observed during the 12 months before screening * Absence of clinical relapses for at least 24 months * Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies * A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: * Is not a WOCBP OR * Is a WOCBP and agrees to use an acceptable contraceptive method Exclusion criteria: * The participant has conditions that would adversely affect study participation such as short life expectancy. * Evidence of infection with human immuodeficiency virus (HIV), transplantation, progressive multifocal leukoencephalopathy (PML), active hepatitis B or C, active or latent tuberculosis or other active infections that would adversely affect study participation. * Persistent chronic or active or recurring system infection, that may adversely affect participation or IMP administration in this study, as judged by the Investigator. * History of malignancy within 5 years prior to screening. * History of alcohol or drug abuse within 1 year prior to screening. * Hospitalized for psychiatric disease within 2 years prior to screening. * Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at screening * Bleeding disorder, known platelet dysfunctionat any time prior to the screening visit * A platelet count \<150 000/μL at the screening visit * A history of significant bleeding event within 6 months prior to screening, according to the Investigator's judgment such as, but not limited to cerebral or gastrointestinal bleeding. * Lymphocyte count below the lower limit of normal at screening. * Recent live (attenuated) vaccine within 2 months before the first treatment visit. * Recent major surgery (within 4 weeks of screening) or planned major surgery during the study. * The participant has received medications/treatments for MS within a specified time frame. * Receiving potent and moderate inducers or inhibitors of cytochrome P450 3A (CYP3A) or potent inhibitors of CYP2C8 hepatic enzymes. * Receiving anticoagulant or antiplatelet therapy (such as aspirin>81mg/day, clopidogrel, warfarin). * Contraindications to magnetic resonance imaging (MRI). The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
As registered. Criteria can change, so ask the trial team or your neurologist.
About this trial
In the sponsor's words
Primary Objective: To determine the efficacy of SAR442168 compared to placebo in delaying disability progression in NRSPMS Secondary Objective: To evaluate efficacy of SAR442168 compared to placebo on clinical endpoints, magnetic resonance imaging (MRI) lesions, cognitive performance, physical function, and quality of life To evaluate safety and tolerability of SAR442168 To evaluate population pharmacokinetics (PK) of SAR442168 and relevant metabolites in NRSPMS and its relationship to efficacy and safety To evaluate pharmacodynamics (PD) of SAR442168
Papers
Results
Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis.N Engl J Med · 2025
Results
Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor, in relapsing multiple sclerosis: a phase 2b, randomised, double-blind, placebo-controlled trial.Lancet Neurol · 2021
Results
Maxwell CR, Turner TJ, Wallstroem E, Patel S, Pappas SC, Lewis JH, Andrade RJ, Syed S. Tolebrutinib liver safety: A detailed overview. Mult Scler Relat Disord. 2026 Jul 23;113:107404. doi: 10.1016/j.msard.2026.107404. Online ahead of print.
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History
Started
Sept 2020
Main results due
Aug 2024
Finished
Aug 2024
Results posted
Jun 2025
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