Phase 3
N=1,131
Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (HERCULES)
Non-relapsing Secondary Progressive Multiple Sclerosis
Bottom Line
View on ClinicalTrials.gov: NCT04411641 ↗Enrolled (actual)
1,131
Serious AEs
13.0%
Results posted
Jun 2025
Primary outcome: Primary: Time to Onset of 6-Month Confirmed Disability Progression (CDP) as Assessed by Expanded Disability Status Scale (EDSS) — 11.97; 12.04 months — p=0.0026
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 3
- Interventions
- Tolebrutinib (Drug); Placebo to match Tolebrutinib (Drug)
- Age
- Adult · 18+ yrs
- Sex
- All
- Sponsor
- Sanofi
- Primary completion
- Aug 2024
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Time to Onset of 6-Month Confirmed Disability Progression (CDP) as Assessed by Expanded Disability Status Scale (EDSS) |
11.97; 12.04 | 0.0026 sig |
| SECONDARY Time to Onset of 3-month Confirmed Disability Progression as Assessed by Expanded Disability Status Scale |
11.96; 12.04 | 0.0134 sig |
| SECONDARY Mean Number of New and/or Enlarging T2-hyperintense Lesions Per Year |
2.948; 1.835 | 0.0110 sig |
| SECONDARY Time to Onset of Sustained 20% Increase in the 9-hole Peg Test (HPT) for at Least 3 Months |
12.39; 12.21 | 0.8428 |
| SECONDARY Time to Onset of Sustained 20% Increase in the Timed 25-foot Walk (T25-FW) for at Least 3 Months |
9.25; 9.54 | 0.0040 sig |
| SECONDARY Time to Onset of 6-month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale |
12.04; 11.89 | 0.0206 sig |
| SECONDARY Percent Change in Brain Volume at EOS Compared to Month 6 |
-0.776; -0.694 | 0.1646 |
| SECONDARY Change From Baseline in Cognitive Function as Assessed by Symbol Digit Modalities Test (SDMT) at EOS |
0.171; 0.136 | — |
| SECONDARY Change From Baseline in Cognitive Function as Assessed by California Verbal Learning Test Second Edition (CVLT-II) at EOS |
13.448; 14.169 | — |
| SECONDARY Change From Baseline in Multiple Sclerosis Quality of Life-54 (MSQoL-54) Questionnaire Score at EOS |
-3.979; -3.455; -4.648; -3.944 | — |
| SECONDARY 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) |
293; 613; 47; 80; 39; 113 | — |
| SECONDARY Maximum Observed Plasma Concentration (Cmax) of Tolebrutinib and M2 Metabolite |
9.94; 27.5 | — |
| SECONDARY Time to Maximum Observed Plasma Concentration (Tmax) of Tolebrutinib and M2 Metabolite |
1.42; 1.52 | — |
| SECONDARY Area Under the Plasma Concentration-time Curve Over the Last 24-hours Dosing Interval (AUC0-24) of Tolebrutinib and M2 Metabolite |
29.6; 84.6 | — |
| SECONDARY Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS |
1.070; 1.900; 5156.900; 3132.250 | — |
| SECONDARY Change From Baseline in Cluster of Differentiation (CD)19+ B Cells at EOS |
10.000; -63.000 | — |
| SECONDARY Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS |
0.350; -0.085; 0.050; -0.240 | — |
Summary
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
Eligibility Criteria
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 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.
Data sourced from ClinicalTrials.gov (NCT04411641). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.