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Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (HERCULES)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04411641
Recruitment Status : Active, not recruiting
First Posted : June 2, 2020
Last Update Posted : February 10, 2023
Sponsor:
Information provided by (Responsible Party):
Sanofi

Study Description
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Brief 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


Condition or disease Intervention/treatment Phase
Secondary Progressive Multiple Sclerosis Drug: Tolebrutinib Drug: Placebo to match Tolebrutinib Phase 3

Detailed Description:

Study duration will vary per participant in this event driven trial with a treatment duration of approximately 24 to 48 months.

Participants completing the treatment period will be proposed to enroll in a separate long term safety study.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1131 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Double-blind, Efficacy and Safety Study Comparing SAR442168 to Placebo in Participants With Nonrelapsing Secondary Progressive Multiple Sclerosis
Actual Study Start Date : September 24, 2020
Estimated Primary Completion Date : August 2024
Estimated Study Completion Date : August 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: SAR442168
Dose 1 of oral SAR442168 once daily
 Drug: Tolebrutinib
Pharmaceutical form: Film-coated tablet Route of administration: Oral
Other Name: SAR442168
Placebo Comparator: Placebo
Placebo tablet to match SAR442168 once daily
 Drug: Placebo to match Tolebrutinib
Pharmaceutical form: Film-coated tablet Route of administration: Oral


Outcome Measures
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Primary Outcome Measures :
  1. 6-month confirmed disability progression (CDP) [ Time Frame: Up to 48 approximately months ]

    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 -



Secondary Outcome Measures :
  1. 3-months change in T25-FW and 9-HPT [ Time Frame: Up to approximately 48 months ]
    Time to onset of composite CDP, confirmed over at least 3 months (3-month CCDP), by the EDSS Plus composite (EDSS score increase, or 20% increase in the T25 FW test, or 20% increase in the 9 hole peg test (9 HPT)

  2. 3-month CDP [ Time Frame: Up to approximately48 months ]
    Time to onset of 3-month CDP as assessed by EDSS score

  3. New and enlarging T2 hyperintense lesions by MRI [ Time Frame: From Baseline up to approximately 48 months ]
    Total number of new or enlarging T2 hyperintense lesions as detected by MRI

  4. Time to onset of confirmed disability improvement (CDI) [ Time Frame: From Baseline up to approximately 48 months ]
    Time to CDI defined as ≥1.0 point decrease on the EDSS score from baseline confirmed over at least 6 months

  5. Brain volume loss (BVL) [ Time Frame: From 6 Months up to approximately 48 months ]
    Percent change in Brain volume loss (BVL) as detected by brain MRI at the EOS compared to month 6

  6. Change in cognitive function [ Time Frame: From Baseline up to approximately 48 months ]
    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) [ Time Frame: From Baseline up to approximately 48 months ]
    Change in Multiple Sclerosis Quality of Life-54 (MSQoL-54) from the baseline through the EOS

  8. Safety and Tolerability [ Time Frame: From Screening until end of study up to approximately 48 months ]
    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 [ Time Frame: Months 6, 9 and 12 ]
    Plasma concentration of SAR442168 and relevant metabolites (population PK assessment) at Months 6, 9, and 12

  10. Change in plasma neurofilament light chain (NfL) [ Time Frame: From Baseline up to approximately 48 months ]
    Change in NfL levels at the EOS compared to baseline

  11. Changes in serum Immunoglobulin level [ Time Frame: From Baseline up to approximately 48 months ]
    Changes in serum Immunoglobulin level at the EOS compared to baseline

  12. Change in lymphocyte phenotype subsets [ Time Frame: From Baseline up to approximately 48 months ]
    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) [ Time Frame: From Baseline up to approximately 48 months ]
    Change in serum chitinase-3 like protein 1 (Chi3L1) at the EOS compared to baseline


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  • 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 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.

Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04411641


Locations
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Sponsors and Collaborators
Sanofi
Investigators
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Study Director: Clinical Sciences & Operations Sanofi
More Information
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Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT04411641    
Other Study ID Numbers: EFC16645
U1111-1246-7768 ( Other Identifier: UTN )
First Posted: June 2, 2020    Key Record Dates
Last Update Posted: February 10, 2023
Last Verified: February 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neoplasm Metastasis
Multiple Sclerosis
Multiple Sclerosis, Chronic Progressive
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
 Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Neoplastic Processes
Neoplasms
Chronic Disease
Disease Attributes