Nonrelapsing secondary progressive multiple sclerosis (NRSPMS) study of Bruton tyrosine kinase (BTK) inhibitor tolebrutinib SAR442168 (HERCULES)

• Register: EUCTR
• Last refreshed on: 19 February 2024
• Main ID: EUCTR2020-000647-30-NL
• Date of registration: 16/09/2020
• Prospective Registration: Yes
• Primary sponsor: Genzyme Corporation
• Public title: Nonrelapsing secondary progressive multiple sclerosis (NRSPMS) study of Bruton tyrosine kinase (BTK) inhibitor tolebrutinib SAR442168 (HERCULES)
• Scientific title: A Phase 3, randomized, double-blind, efficacy and safety study comparing SAR442168 to placebo in participants with nonrelapsing secondary progressive multiple sclerosis - HERCULES
• Date of first enrolment: 23/12/2020
• Target sample size: 1700
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2020-000647-30
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belarus, Belgium, Bulgaria, Canada, Chile, China, Czech Republic, Czechia, Denmark, Finland, France, Germany, Greece, Hungary, India, Israel, Italy, Japan, Lithuania, Netherlands, Norway, Poland, Portugal, Romania, Russian Federation, Spain, Türkiye, Ukraine, United Kingdom, United States

Contacts

• Name: Team manager
• Affiliation: Sanofi B.V.

• Name: Team manager
• Affiliation: Sanofi B.V.

Key inclusion & exclusion 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
- Participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a woman of child bearing potential (WOCBP)
OR
- Is a WOCBP and agrees to use an acceptable contraceptive method
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 1700
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
- The participant has conditions that would adversely affect study participation such as short life expectancy.
- History of organ transplant.
- 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 alchohol 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
- A bleeding disorder or known platelet dysfunction at 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 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).
NOTE: Other Inclusion/Exclusion criteria may apply.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Non-relapsing Secondary Progressive Multiple Sclerosis
MedDRA version: 21.1 Level: PT Classification code 10063400 Term: Secondary progressive multiple sclerosis System Organ Class: 10029205 - Nervous system disorders

Intervention(s)

Product Code: SAR442168
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Not available
CAS Number: 1971920-73-6
Current Sponsor code: SAR442168
Other descriptive name: PRN2246
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 60-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: - To evaluate efficacy of SAR442168 compared to placebo on clinical endpoints, magnetic resonsnce
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 in NRSPMS and its relationship to efficacy and safety
- To evaluate pharmacodynamics (PD) of SAR442168

Timepoint(s) of evaluation of this end point: Up to approximately 48 months

Primary end point(s): 6-month confirmed disability progression (CDP) ; Time to onset of 6 months CDP defined as follows:
-Increase of =1.0 point from the baseline expanded disability status scale (EDSS) score when the baseline score is =5.0, or
-Increase of =0.5 point when the baseline EDSS score is >5.0

Main Objective: To determine the efficacy of SAR442168 compared to placebo in delaying disability progression in
NRSPMS

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: 1, 2 : Up to approximately 48 months
3, 4, 5, 6, 7, 10, 11, 12, 13 : From Baseline up to approximately 48 months
8 : From Screening until end of study up to approximately 48 months
9 : Months 6, 9 and 12

Secondary end point(s): 1 - 3-months change in T25-FW and 9-HPT ; Time to onset of sustained 20% increase in the timed 25 foot walk (T25-FW) and the 9-hole peg test (9-HPT) for at least 3 months
2 - 3-month CDP ; Time to onset of 3-month CDP as assessed by EDSS score
3 - T2 hyperintense lesion by MRI ; Total number of new or enlarging T2 hyperintense lesions as detected by MRI
4 - Time to confirmed disability improvement (CDI) ; Time to onset of CDI defined as =1.0 point decrease on the EDSS score from baseline confirmed over at least 6 months
5 - Brain volume loss (BVL) ; Percent change in Brain volume loss (BVL) as detected by brain MRI at the EOS compared to month 6
6 - Change in cognitive function ; Change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test (SDMT) and by the California Verbal Learning Test (CVLT-II)
7 - Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) ; Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS
8 - Safety and Tolerability ; Number of participants with adverse events (AEs), Serious AEs, AEs leading to permanent study intervention discontinuation, and adverse events of special interest (AESI)
9 - Population pharmacokinetics ; Plasma concentration of SAR442168 and relevant metabolites (population PK assessment) at Months 6, 9, and 12
10 - Change in plasma neurofilament light chain (NfL) ; Change in NfL levels at the EOS compared to baseline
11 - Changes in serum Immunoglobulin level ; Changes in serum Immunoglobulin level at the EOS compared to baseline
12 - Change in lymphocyte phenotype subsets ; Change in lymphocyte phenotype subsets in whole blood at the EOS compared to baseline in a subset of participants
13 - Change in serum chitinase-3 like protein 1 (Chi3L1) ; Change in serum chitinase-3 like protein 1 (Chi3L1) at the EOS compared to baseline

Secondary ID(s)

EFC16645

2020-000647-30-BG

Source(s) of Monetary Support

Genzyme Corporation

Ethics review

Status: Approved
Approval date: 23/12/2020
Contact: