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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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04411641
Recruitment Status : Recruiting
First Posted : June 2, 2020
Last Update Posted : October 3, 2022
Sponsor:
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE May 28, 2020
First Posted Date  ICMJE June 2, 2020
Last Update Posted Date October 3, 2022
Actual Study Start Date  ICMJE September 24, 2020
Estimated Primary Completion Date August 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 28, 2020)
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 -
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 3, 2021)
  • 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)
  • 3-month CDP [ Time Frame: Up to approximately48 months ]
    Time to onset of 3-month CDP as assessed by EDSS score
  • 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
  • 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
  • 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
  • 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)
  • 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
  • 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)
  • 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
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: May 28, 2020)
  • 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)
  • 3-month CDP [ Time Frame: Up to approximately48 months ]
    Time to onset of 3-month CDP as assessed by EDSS score
  • 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
  • Time to 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
  • 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
  • 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) -
  • 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
  • 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)
  • Population pharmacokinetics [ Time Frame: Months 6, 9 and 12 ]
    Plasma concentration of SAR442168 (population PK assessment) at Months 6, 9, and 12
  • 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 -
  • 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
  • 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
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168)
Official Title  ICMJE A Phase 3, Randomized, Double-blind, Efficacy and Safety Study Comparing SAR442168 to Placebo in Participants With Nonrelapsing Secondary Progressive Multiple Sclerosis
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

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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Secondary Progressive Multiple Sclerosis
Intervention  ICMJE
  • Drug: Tolebrutinib
    Pharmaceutical form: Film-coated tablet Route of administration: Oral
    Other Name: SAR442168
  • Drug: Placebo to match Tolebrutinib
    Pharmaceutical form: Film-coated tablet Route of administration: Oral
Study Arms  ICMJE
  • Experimental: SAR442168
    Dose 1 of oral SAR442168 once daily
    Intervention: Drug: Tolebrutinib
  • Placebo Comparator: Placebo
    Placebo tablet to match SAR442168 once daily
    Intervention: Drug: Placebo to match Tolebrutinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 28, 2020)
1290
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2024
Estimated Primary Completion Date August 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Trial Transparency email recommended (Toll free number for US & Canada) 800-633-1610 ext option 6 Contact-US@sanofi.com
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belarus,   Belgium,   Bulgaria,   Canada,   China,   Czechia,   Denmark,   Finland,   France,   Germany,   Greece,   Hungary,   India,   Israel,   Italy,   Japan,   Lithuania,   Netherlands,   Norway,   Poland,   Portugal,   Romania,   Russian Federation,   Spain,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04411641
Other Study ID Numbers  ICMJE EFC16645
U1111-1246-7768 ( Other Identifier: UTN )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Current Responsible Party Sanofi
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Sanofi
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date September 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP